EP3060237B1 - Modified reprogramming protein for use in treating a cancer - Google Patents
Modified reprogramming protein for use in treating a cancer Download PDFInfo
- Publication number
- EP3060237B1 EP3060237B1 EP14855040.3A EP14855040A EP3060237B1 EP 3060237 B1 EP3060237 B1 EP 3060237B1 EP 14855040 A EP14855040 A EP 14855040A EP 3060237 B1 EP3060237 B1 EP 3060237B1
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- modified
- protein
- transduction reagent
- protein transduction
- cells
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- C12N2506/00—Differentiation of animal cells from one lineage to another; Differentiation of pluripotent cells
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Definitions
- the present invention relates generally to compositions or proteins for use in a method of cancer treatment in a subject in need thereof.
- the present invention relates to compositions or isolated protein transduction reagent-modified reprogramming proteins for protein-induction of cell conversion in vivo for use in a method of cancer treatment in a subject in need thereof.
- WO 2012/151234 A2 discloses the use of a composition comprising protein-induced pluripotent stem cells modified by reprogramming proteins like Oct4, Sox4, Nanog being non-covalently bound to QQ-reagents for use in treating cancer.
- WO 2012/151234 A2 thereby relates to the use for in vitro cell modifications, whereby the modified cells are thereafter administered to a subject.
- WO 2010/075575 A1 and WO 2013/013105 A2 disclose the use of a composition comprising modified reprogramming proteins like Oct4, Sox4, Nanog or Sox9, Sox6, c-Myc, respectively, being non-covalently or covalently bound to a cationic lipid polymer (i.e. an "onecomponent transduction reagent") for use in treating cancer and other diseases.
- a cationic lipid polymer i.e. an "onecomponent transduction reagent
- compositions for use in methods of treating cancer of a subject in need thereof are provided according to aspects of the present invention which include administering a pharmaceutical composition comprising a protein transduction reagent-modified reprogramming protein to the subject, wherein the protein transduction reagent is non-covalently bound to the reprogramming protein and wherein the protein transduction reagent comprises a cation reagent and a lipid.
- the protein transduction reagent-modified reprogramming protein is selected from Sox2, Oct4 and Nanog.
- compositions for use in methods of treating a subject in need thereof are provided according to aspects of the present invention which include administering a pharmaceutical composition comprising a protein transduction reagent-modified reprogramming protein, selected from Sox2, Oct4 and Nanog, to the subject, wherein the protein transduction reagent is non-covalently bound to the reprogramming protein and wherein the protein transduction reagent comprises a cation reagent and a lipid, wherein the subject has a cancer disease.
- a pharmaceutical composition comprising a protein transduction reagent-modified reprogramming protein, selected from Sox2, Oct4 and Nanog
- compositions for use in methods of treating a subject having cancer are provided according to aspects of the present invention which include administering a pharmaceutical composition including a protein transduction reagent-modified reprogramming protein selected from the group consisting of: protein transduction reagent-modified Sox2, protein transduction reagent-modified Oct4 and protein transduction reagent-modified Nanog.
- a protein transduction reagent-modified reprogramming protein selected from the group consisting of: protein transduction reagent-modified Sox2, protein transduction reagent-modified Oct4 and protein transduction reagent-modified Nanog.
- compositions for use in methods of treating a subject having cancer are provided according to aspects of the present invention which include administering a pharmaceutical composition including protein transduction reagent-modified Sox2, protein transduction reagent-modified Oct4 and protein transduction reagent-modified Nanog.
- compositions for use in methods of treating a subject having a brain tumor or breast cancer which include administering a pharmaceutical composition including a protein transduction reagent-modified reprogramming protein selected from the group consisting of: protein transduction reagent-modified Sox2, protein transduction reagent-modified Oct4 and protein transduction reagent-modified Nanog.
- a protein transduction reagent-modified reprogramming protein selected from the group consisting of: protein transduction reagent-modified Sox2, protein transduction reagent-modified Oct4 and protein transduction reagent-modified Nanog.
- compositions for use in methods of treating a subject having a brain tumor or breast cancer which include administering a pharmaceutical composition including protein transduction reagent-modified Sox2, protein transduction reagent-modified Oct4 and protein transduction reagent-modified Nanog.
- Use in methods according to the present invention allow of delivery of protein-transduction reagent-modified reprogramming proteins to cancer cells, such as tumor cells, as well as diseased cells of diseased tissues.
- Use in methods according to aspects of the present invention provide in vivo conversion of diseased cells into normal cells via protein-induced in situ cell reprogramming. Use in methods according to aspects of the present invention provide in vivo conversion of cancer cells into normal cells via protein-induced in situ cell reprogramming.
- Isolated protein-transduction reagent-modified reprogramming proteins are provided for use in a method of treating cancer by reprogramming cancer cells in situ into stem cells or transient protein-induced multipotent stem cells that are then induced to differentiate into normal cells in the tissue where the cancer cells or diseased cells were located is provided according to aspects of the present invention.
- One or more isolated protein transduction reagent-modified reprogramming proteins are provided for use in methods of treating cancer according to aspects of the present invention which treat the cancer in vivo not by killing the cancer cells but instead by converting the cancer cells into non-cancerous cells by administration, such as systemic or local administration, of the one or more isolated protein transduction reagent-modified reprogramming proteins.
- RNA Interference RNA Interference
- DNA Press LLC Eagleville, PA, 2003
- Herdewijn, P. (Ed.) Oligonucleotide Synthesis: Methods and Applications, Methods in Molecular Biology, Humana Press, 2004 ; A. Nagy, M. Gertsenstein, K. Vintersten, R. Behringer, Manipulating the Mouse Embryo: A Laboratory Manual, 3rd edition, Cold Spring Harbor Laboratory Press; December 15, 2002, ISBN-10: 0879695919 ; Kursad Turksen (Ed.), Embryonic stem cells: methods and protocols in Methods Mol Biol. 2002;185, Humana Press ; Current Protocols in Stem Cell Biology, ISBN: 9780470151808 .
- compositions or isolated protein transduction reagent-modified reprogramming proteins for use in methods according to aspects of the present invention provide protein-induced cell reprogramming in vivo to treat cancer in a subject in need thereof.
- compositions or isolated protein transduction reagent-modified reprogramming proteins for use in methods according to aspects of the present invention provide for conversion of cancer cells into normal cells by introducing one or more QQ-modified reprogramming proteins into the cancer cells in vivo without introduction of nucleic acids encoding the one or more reprogramming proteins.
- compositions or isolated protein transduction reagent-modified reprogramming proteins for use in methods according to aspects of the present invention provide for conversion of cancer cells into non-cancerous cells by introducing one or more QQ-modified reprogramming proteins into the cancer cells in vivo without introduction of nucleic acids encoding the one or more reprogramming proteins.
- compositions for use in methods of treating cancer of a subject in need thereof are provided according to aspects of the present invention which include systemically and/or locally administering a pharmaceutical composition comprising a protein transduction reagent-modified reprogramming protein to the subject, wherein the protein transduction reagent is non-covalently bound to the reprogramming protein and wherein the protein transduction reagent comprises a cation reagent and a lipid.
- a “protein transduction reagent-modified reprogramming protein” is a reprogramming protein that has been treated with the protein transduction reagent, also termed a "QQ reagent” herein.
- the term “protein transduction reagent” refers to a composition effective to enable a protein non-covalently bound to the protein transduction reagent to be delivered into mammalian cells and once present in mammalian cells, to dissociate from the protein to allow proper delivery of the protein to its proper subcellular location.
- the protein transduction reagent also termed a "QQ reagent” herein, includes at least one cation reagent, at least one lipid, and optionally an enhancer.
- QQ modified reprogramming protein and grammatical variants thereof as used herein is equivalent to "protein transduction reagent-modified reprogramming protein” and grammatical variants thereof as used herein.
- QQ protein signifies that the protein is modified by treatment with a protein transduction reagent and is a "protein transduction reagent-modified reprogramming protein.
- QQ-SON refers to a mixture of Sox2, Oct4 and Nanog proteins modified by treatment with a protein transduction reagent as described herein to produce protein transduction reagent-modified reprogramming Sox2, Oct4 and Nanog proteins.
- PEI polyethylenimine
- the lipid can be any lipid known to those of skill in the art to have the same general properties as those listed herein.
- lipids examples include, but are not limited to, DOTMA (N-1(-(2,3-dioleyloxy)propyl-N,N,N-trimethyl-ammonium chloride; DOGS (dioctadecylamido-glycylspermine); DOTAP, 1,2-dioleoyl-3-trimethylammonium-propane; DOPE, 1,2-dioleoyl- sn -glycero-3-phosphoethanolamine; POPC, 1-palmitoyl-2-oleoyl- sn -glycero-3-phosphocholine; and DMPE 1,2-dimyristoyl- sn -glycero-3-phosphocholine.
- DOTMA N-1(-(2,3-dioleyloxy)propyl-N,N,N-trimethyl-ammonium chloride
- DOGS dioctadecylamido-glycylspermine
- DOTAP 1,
- the protein transduction reagent includes polyethylenimine as a cation reagent and the lipid is DOTAP or DOTMA and DOPE or DOGS; POPC and DMPE; or DOTAP or DOTMA, DOPE or DOGS, POPC and DMPE.
- the protein transduction reagent is QQ1a, QQ2a, QQ3a, QQ4a, QQ5a, QQ6a, QQ7a, QQ8a, QQ9a as described in Table 1.
- the optional enhancer can be any enhancer that significantly enhances cell loading of cationized proteins.
- enhancers in cell cultures include, but are not limited to MG132, protease inhibitor, CaCl 2 , DMSO and growth factors.
- Other enhancers can also be used, including, but not limited to, cell membrane surfactants.
- the reagent can also include stabilizers and other inert carriers that do not affect the function of the reagent. As shown in Table 1, the concentrations and specific compounds utilized can vary.
- reprogramming protein refers to a DNA binding transcription factor protein, or effective portion thereof, which affects transcription of a gene and which induces a change from a first differentiated cell type to a second, different, differentiated cell type.
- the change from a first differentiated cell type to a second, different, differentiated cell type typically proceeds through an intermediate, less differentiated, cell type, such as a transient stem cell including protein-induced pluripotent stem cells.
- Reprogramming proteins and nucleic acids that encode them have been isolated from humans and other species.
- Reprogramming proteins include Asc1, Ascl1, Brca-11, Brn2, C/EBP ⁇ , CEBP ⁇ , c-MYC, Dlx2, EKLF, Erg1, Er71, Fli1, Foxal, Foxa2, Foxa3, FoxC1, FoxC2, FOXG1, FOXP3, Gata1, Gata2, Gata3, Gata4, Gata6, GFI1, Hand2, Hb9, Hey1, Hey2, HNF4A, Hnfla, Klf4, Lhx3, LIN28A, Lmxla, Lsll, MafA, MEF2c, Mytll, MYF5, MyoD, NAB2, Nanog, NeuroD1, NEUROG2, NEUROG3, Nurr1, Oct4, Pdxl, Pax4, PAX5, Pax6, Prdm16, PU.1, ROR gamma, Runx2, SLC7A10, Slug, Sox2, Sox5, Sox6, Sox7, Sox9, Sox18, Stat5a, T-be
- a reprogramming protein to be QQ-modified is obtained by methods such as isolation, synthesis, or recombinant expression of a nucleic acid encoding the reprogramming protein. Such proteins may also be obtained commercially.
- nucleic acid refers to RNA or DNA molecules having more than one nucleotide in any form including single-stranded, double-stranded, oligonucleotide or polynucleotide.
- nucleotide sequence refers to the ordering of nucleotides in an oligonucleotide or polynucleotide in a single-stranded form of nucleic acid.
- Recombinant expression of a reprogramming protein to be QQ-modified includes expression of a nucleic acid encoding the protein wherein the nucleic acid is included in an expression construct.
- a host cell may be transfected with the expression construct encoding the desired reprogramming protein such that the reprogramming protein is expressed in the cell.
- expression construct and "expression cassette” are used herein to refer to a double-stranded recombinant DNA molecule containing a desired nucleic acid coding sequence for a reprogramming factor to be expressed and containing one or more regulatory elements necessary or desirable for the expression of the operably linked coding sequence.
- Expression constructs operable to express a desired protein include, for example, in operable linkage: a promoter, a DNA sequence encoding a desired protein and a transcription termination site.
- regulatory element refers to a nucleotide sequence which controls some aspect of the expression of nucleic acid sequences.
- exemplary regulatory elements illustratively include an enhancer, an internal ribosome entry site (IRES), an intron; an origin of replication, a polyadenylation signal (polyA), a promoter, a transcription termination sequence, and an upstream regulatory domain, which contribute to the replication, transcription, posttranscriptional processing of a nucleic acid sequence.
- IRS internal ribosome entry site
- polyA polyadenylation signal
- promoter a transcription termination sequence
- upstream regulatory domain which contribute to the replication, transcription, posttranscriptional processing of a nucleic acid sequence.
- operably linked refers to a nucleic acid in functional relationship with a second nucleic acid.
- a regulatory element included in an expression cassette is a promoter in particular aspects.
- promoter is well-known in the art and refers to one or more DNA sequences operably linked to a nucleic acid sequence to be transcribed and which bind an RNA polymerase and allow for initiation of transcription.
- a promoter is typically positioned upstream (5') of a nucleic acid encoding a peptide or protein to be expressed.
- An included promoter can be a constitutive promoter or can provide inducible expression.
- One of skill in the art is familiar with various well-known promoters and is able to select a promoter suitable for use in expressing a peptide or protein in a particular environment, such as in a specified cell type.
- suitable promoters include, but are not limited to, an ADH1 promoter, a PGK1 promoter, an ENO promoter, a PYK1 promoter and the like; or a regulatable promoter such as a GAL1 promoter, a GAL 10 promoter, an ADH2 promoter, a PH05 promoter, a CUP1 promoter, a GAL7 promoter, a MET25 promoter, a MET3 promoter, a CYC1 promoter, a HIS 3 promoter, an ADH1 promoter, a PGK promoter, a GAPDH promoter, an ADC1 promoter, a TRP1 promoter, a URA3 promoter, a LEU2 promoter, an ENO promoter, a TP1 promoter, and AOX1.
- a regulatable promoter such as a GAL1 promoter, a GAL 10 promoter, an ADH2 promoter, a PH05 promoter, a CUP1
- suitable promoters include, but are not limited to, a bacteriophage T7 RNA polymerase promoter; a trp promoter; a lac operon promoter; a trc promoter; a tac promoter,; an araBAD promoter; an ssaG promoter; a pagC promoter, a sigma70 promoter, a dps promoter, an spv promoter, an SPI-2 promoter; an actA promoter, an rps M promoter; a tetracycline promoter, an SP6 promoter, a bacteriophage T3 promoter, a gpt promoter and a bacteriophage lambda P promoter.
- promoters that can be included in an expression construct include, but are not limited to, cytomegalovirus immediate early promoter; herpes simplex virus thymidine kinase promoter; early and late SV40 promoters; a phosphoglycerate kinase (PGK) promoter; a promoter present in long terminal repeats from a retrovirus; and a mouse metallothionein-I promoter, a beta-actin promoter, a ROSA26 promoter, a heat shock protein 70 (Hsp70) promoter, an EF-1 alpha gene encoding elongation factor 1 alpha (EF1) promoter, an eukaryotic initiation factor 4A (eIF-4A1) promoter, a chloramphenicol acetyltransferase (CAT) promoter and the long terminal repeat region of Rous Sarcoma virus (RSV promoter).
- cytomegalovirus immediate early promoter herpes simplex virus thymidine kinas
- one or more enhancer sequences may be included such as, but not limited to, cytomegalovirus (CMV) early enhancer element and an SV40 enhancer element.
- CMV cytomegalovirus
- Additional included sequences include an intron sequence such as the beta globin intron or a generic intron, a transcription termination sequence, and an mRNA polyadenylation (pA) sequence such as, but not limited to SV40-pA, beta-globin-pA and SCF-pA.
- intron sequence such as the beta globin intron or a generic intron
- pA mRNA polyadenylation
- An expression construct may include sequences necessary for amplification in bacterial cells, such as a selection marker (e.g. kanamycin or ampicillin resistance gene) and a replicon.
- a selection marker e.g. kanamycin or ampicillin resistance gene
- a replicon e.g. kanamycin or ampicillin resistance gene
- IRES internal ribosome entry site
- Pelletier J. et al., Nature, 334:320-325, 1988 ; Vagner, S. et al., EMBO Rep., 2:893-898, 2001 ; and Hellen, C. U. et al, Genes Dev. 15:1593-1612, 2001 .
- transcription termination site refers to a DNA sequence operable to terminate transcription by an RNA polymerase.
- a transcription termination site is generally positioned downstream (3') of a nucleic acid encoding a peptide or protein to be expressed.
- a leader sequence is optionally included in an expression construct.
- Codon optimization of a nucleic acid encoding a desired protein may be used to improve expression in a particular expression system, for example by improving the efficiency of translation.
- a selected nucleic acid encoding a desired protein may be codon optimized for expression in any designated host cell, prokaryotic or eukaryotic, such as, but not limited to, bacteria, insect cells, yeast, fungus, bird eggs and mammalian cells.
- An expressed protein optionally includes an N-terminal element such as a leader sequence and/or N-terminal methionine.
- nucleic acid sequences encoding additional proteins can be included in an expression vector.
- a nucleic acid sequence encoding a reporter including, but not limited to, beta-galactosidase, green fluorescent protein and antibiotic resistance reporters is optionally included.
- a his-tag, GST-tag or MBP-tag is optionally included.
- a nucleic acid encoding a reprogramming protein can be cloned into an expression vector for transformation into prokaryotic or eukaryotic cells and expression of the encoded peptides and/or protein(s).
- expression vectors are defined as polynucleotides which, when introduced into an appropriate host cell, an expression system, can be transcribed and translated, producing the encoded polypeptide(s).
- Expression vectors are known in the art and include plasmids, cosmids, viruses and bacteriophages, for example.
- Expression vectors can be prokaryotic vectors, insect vectors, or eukaryotic vectors, for example.
- an expression construct including, in operable linkage: a promoter, a DNA sequence encoding a desired protein and a transcription termination site, is included in a plasmid, cosmid, virus or bacteriophage expression vector.
- Any suitable expression vector/host cell system can be used for expression of a transcription factor for administration to a subject according to aspects of the present invention.
- Expression of a reprogramming protein using a recombinant expression vector is accomplished by introduction of the expression vector into an eukaryotic or prokaryotic host cell expression system such as an insect cell, mammalian cell, yeast cell, fungus, bird egg, bacterial cell or any other single or multicellular organism recognized in the art.
- an eukaryotic or prokaryotic host cell expression system such as an insect cell, mammalian cell, yeast cell, fungus, bird egg, bacterial cell or any other single or multicellular organism recognized in the art.
- Host cells containing the recombinant expression vector are maintained under conditions wherein the desired protein is produced.
- Host cells may be cultured and maintained using known cell culture techniques such as described in Celis, Julio, ed., 1994, Cell Biology Laboratory Handbook, Academic Press, N.Y .
- Various culturing conditions for these cells including media formulations with regard to specific nutrients, oxygen, tension, carbon dioxide and reduced serum levels, can be selected and optimized by one of skill in the art.
- Bacterial cells can be used as the host cells to produce reprogramming proteins.
- Recombinant protein expression in bacterial cells and purification of the produced protein may be performed using known protocols, such as described in Paulina Balbás, Argelia Lorence ed., 2004, Recombinant Gene Expression: Reviews and Protocols, Humana Press, New Jersey ; Peter E. Vaillancourt, 2003, E. Coli Gene Expression Protocols, Springer Science & Business Media .
- recombinantly produced reprogramming proteins are purified to remove endotoxin when an endotoxin producing host cell type is used.
- an additional washing step can be added during protein purification stage using 10 column volume of 0.2% of Triton X114 to remove endotoxin from bacterially expressed recombinant reprogramming proteins.
- ClearColiTM BL21(DE3) a genetically modified bacterial strain, ClearColiTM BL21(DE3) can be used as host cells such that no endotoxin removal is required.
- any of the well-known procedures for introducing recombinant nucleic acids into host cells may be used, such as calcium phosphate transfection, polybrene, protoplast fusion, electroporation, sonoporation, liposomes and microinjection, examples of which are described in Sambrook et al., Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press, 2001 ; and Ausubel, F. et al., (Eds.), Current Protocols in Molecular Biology, 2014 .
- Cell free expression systems are optionally used to express a reprogramming protein, such as described in Ausubel, F. et al., (Eds.), Current Protocols in Molecular Biology, 2014 .
- Human reprogramming proteins shown herein as SEQ ID NOs: 1-63, and encoded by the nucleic acid sequences of SEQ ID NOs: 65-127, and variants thereof, can be used in methods according to aspects described herein.
- variant refers to a variation of a nucleic acid sequence encoding a reprogramming protein or a variation of a reprogramming protein in which one or more nucleotides or amino acid residues have been modified by nucleotide or amino acid substitution, addition, or deletion while retaining the function of the reference nucleic acid sequence or reprogramming protein. Variants of a nucleic acid sequence or reprogramming protein described herein are characterized by conserved functional properties compared to the corresponding nucleic acid sequence or reprogramming protein.
- Mutations can be introduced using standard molecular biology techniques, such as chemical synthesis, site-directed mutagenesis and PCR-mediated mutagenesis.
- amino acid mutations can be introduced without altering the functional properties of a desired reprogramming protein.
- amino acid substitutions, additions, or deletions can be made without altering the functional properties of a desired reprogramming protein.
- Biological activity of a reprogramming protein variant is readily determined by one of skill in the art, for instance using any of the functional assays described herein or other functional assays known in the art.
- Variants of a reprogramming protein described herein are characterized by conserved functional properties compared to the corresponding reprogramming protein and have 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or greater identity to the amino acid sequence of a reference reprogramming protein.
- amino acid similarity When comparing a reference reprogramming protein to a variant, amino acid similarity may be considered in addition to identity of amino acids at corresponding positions in an amino acid sequence. "Amino acid similarity" refers to amino acid identity and conservative amino acid substitutions in a putative homologue compared to the corresponding amino acid positions in a reference protein.
- Variants of a reprogramming protein described herein are characterized by conserved functional properties compared to the corresponding reprogramming protein and have 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or greater similarity to the amino acid sequence of a reference reprogramming protein.
- Conservative amino acid substitutions are art recognized substitutions of one amino acid for another amino acid having similar characteristics.
- each amino acid may be described as having one or more of the following characteristics: electropositive, electronegative, aliphatic, aromatic, polar, hydrophobic and hydrophilic.
- a conservative substitution is a substitution of one amino acid having a specified structural or functional characteristic for another amino acid having the same characteristic.
- Acidic amino acids include aspartate, glutamate; basic amino acids include histidine, lysine, arginine; aliphatic amino acids include isoleucine, leucine and valine; aromatic amino acids include phenylalanine, glycine, tyrosine and tryptophan; polar amino acids include aspartate, glutamate, histidine, lysine, asparagine, glutamine, arginine, serine, threonine and tyrosine; and hydrophobic amino acids include alanine, cysteine, phenylalanine, glycine, isoleucine, leucine, methionine, proline, valine and tryptophan; and conservative substitutions include substitution among amino acids within each group. Amino acids may also be described in terms of relative size, alanine, cysteine, aspartate, glycine, asparagine, proline, threonine, serine, valine, all typically considered to be small.
- a variant can include synthetic amino acid analogs, amino acid derivatives and/or nonstandard amino acids, illustratively including, without limitation, alpha-aminobutyric acid, citrulline, canavanine, cyanoalanine, diaminobutyric acid, diaminopimelic acid, dihydroxyphenylalanine, djenkolic acid, homoarginine, hydroxyproline, norleucine, norvaline, 3-phosphoserine, homoserine, 5-hydroxytryptophan, 1-methylhistidine, 3-methylhistidine, and ornithine.
- synthetic amino acid analogs amino acid derivatives and/or nonstandard amino acids
- amino acid derivatives illustratively including, without limitation, alpha-aminobutyric acid, citrulline, canavanine, cyanoalanine, diaminobutyric acid, diaminopimelic acid, dihydroxyphenylalanine, djenkolic acid, homoarginine, hydroxyproline, norleucine
- Percent identity is determined by comparison of amino acid or nucleic acid sequences, including a reference amino acid or nucleic acid sequence and a putative homologue amino acid or nucleic acid sequence.
- the sequences are aligned for optimal comparison purposes (e.g., gaps can be introduced in the sequence of a first amino acid or nucleic acid sequence for optimal alignment with a second amino acid or nucleic acid sequence).
- the amino acid residues or nucleotides at corresponding amino acid positions or nucleotide positions are then compared. When a position in the first sequence is occupied by the same amino acid residue or nucleotide as the corresponding position in the second sequence, then the molecules are identical at that position.
- the two sequences compared are generally the same length or nearly the same length.
- the determination of percent identity between two sequences can also be accomplished using a mathematical algorithm.
- Algorithms used for determination of percent identity illustratively include the algorithms of S. Karlin and S. Altshul, PNAS, 90:5873-5877, 1993 ; T. Smith and M. Waterman, Adv. Appl. Math. 2:482-489, 1981 , S. Needleman and C. Wunsch, J. Mol. Biol., 48:443-453, 1970 , W. Pearson and D.
- a non-limiting example of a mathematical algorithm utilized for the comparison of two sequences is the algorithm of Karlin and Altschul, 1990, PNAS 87:2264-2268 , modified as in Karlin and Altschul, 1993, PNAS. 90:5873-5877 .
- Such an algorithm is incorporated into the NBLAST and XBLAST programs of Altschul et al., 1990, J. Mol. Biol. 215:403 .
- Gapped BLAST is utilized as described in Altschul et al., 1997, Nucleic Acids Res. 25:3389-3402 .
- PSI BLAST is used to perform an iterated search which detects distant relationships between molecules.
- the default parameters of the respective programs e.g., of XBLAST and NBLAST.
- a mathematical algorithm utilized for the comparison of sequences is the algorithm of Myers and Miller, 1988, CABIOS 4:11-17 . Such an algorithm is incorporated in the ALIGN program (version 2.0) which is part of the GCG sequence alignment software package. When utilizing the ALIGN program for comparing amino acid sequences, a PAM120 weight residue table, a gap length penalty of 12, and a gap penalty of 4 is used.
- the percent identity between two sequences is determined using techniques similar to those described above, with or without allowing gaps. In calculating percent identity, typically only exact matches are counted.
- nucleic acid or amino acid mutations can be introduced without altering the functional properties of a given nucleic acid or protein, respectively.
- human reprogramming proteins shown herein as SEQ ID NOs: 1-63 are encoded by the nucleic acid sequences of SEQ ID NOs: 65-127. It is appreciated that due to the degenerate nature of the genetic code, alternate nucleic acid sequences encode a particular reprogramming protein, and that such alternate nucleic acids may be expressed to produce the desired reprogramming protein.
- nucleic acid refers to Watson-Crick base pairing between nucleotides and specifically refers to nucleotides hydrogen bonded to one another with thymine or uracil residues linked to adenine residues by two hydrogen bonds and cytosine and guanine residues linked by three hydrogen bonds.
- a nucleic acid includes a nucleotide sequence described as having a "percent complementarity" to a specified second nucleotide sequence.
- a nucleotide sequence may have 80%, 90%, or 100% complementarity to a specified second nucleotide sequence, indicating that 8 of 10, 9 of 10 or 10 of 10 nucleotides of a sequence are complementary to the specified second nucleotide sequence.
- nucleotide sequence 3'-TCGA-5' is 100% complementary to the nucleotide sequence 5'-AGCT-3'. Further, the nucleotide sequence 3'-TCGA-5' is 100% complementary to a region of the nucleotide sequence 5'-TTAGCTGG-3'.
- hybridization and “hybridizes” refer to pairing and binding of complementary nucleic acids. Hybridization occurs to varying extents between two nucleic acids depending on factors such as the degree of complementarity of the nucleic acids, the melting temperature, Tm, of the nucleic acids and the stringency of hybridization conditions, as is well known in the art.
- stringency of hybridization conditions refers to conditions of temperature, ionic strength, and composition of a hybridization medium with respect to particular common additives such as formamide and Denhardt's solution. Determination of particular hybridization conditions relating to a specified nucleic acid is routine and is well known in the art, for instance, as described in J. Sambrook and D.W.
- High stringency hybridization conditions are those which only allow hybridization of substantially complementary nucleic acids. Typically, nucleic acids having about 85-100% complementarity are considered highly complementary and hybridize under high stringency conditions. Intermediate stringency conditions are exemplified by conditions under which nucleic acids having intermediate complementarity, about 50-84% complementarity, as well as those having a high degree of complementarity, hybridize. In contrast, low stringency hybridization conditions are those in which nucleic acids having a low degree of complementarity hybridize.
- specific hybridization and “specifically hybridizes” refer to hybridization of a particular nucleic acid to a target nucleic acid without substantial hybridization to nucleic acids other than the target nucleic acid in a sample.
- Hybridization and conditions to achieve a desired hybridization stringency are described, for example, in Sambrook et al., Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press, 2001 ; and Ausubel, F. et al., (Eds.), Short Protocols in Molecular Biology, Wiley, 2002 .
- An example of high stringency hybridization conditions is hybridization of nucleic acids over about 100 nucleotides in length in a solution containing 6X SSC, 5X Denhardt's solution, 30% formamide, and 100 micrograms/ml denatured salmon sperm at 37°C overnight followed by washing in a solution of 0.1X SSC and 0.1% SDS at 60°C for 15 minutes.
- SSC is 0.15M NaCl/0.015M Na citrate.
- Denhardt's solution is 0.02% bovine serum albumin/0.02% FICOLL/0.02% polyvinylpyrrolidone.
- a reprogramming protein modified by QQ is an isolated protein according to aspects of the present invention.
- isolated protein indicates that the protein has been separated from biological materials, such as cells, cellular debris and other proteins, which may be present in the system in which the protein is produced.
- isolated protein may, but does not necessarily, indicate that the protein is purified.
- Purified protein included in methods and compositions of the present invention contains least about 1 - 100% of the mass, by weight, such as about 25%, 50%, 75%, 85%, 95%, 99% or greater than about 99% of the mass, by weight, of the protein included.
- subject refers to an individual in need of treatment for a disease or injury responsive to the beneficial effects of cell reprogramming, and generally includes mammals and birds, such as, but not limited to, humans, other primates, cats, dogs, sheep, cows, goats, horses, pigs, poultry, rabbits and rodents, such as rats, mice and guinea pigs. According to aspects of the present invention, the subject is human.
- treating and “treatment” used to refer to treatment of a condition characterized by damaged, and/or defective cells such as a disease or injury of a subject include: inhibiting or ameliorating the disease or injury in the subject, such as slowing progression of the disease and/or reducing or ameliorating a sign or symptom of the disease or injury.
- Conditions characterized by angiogenesis are treated according to aspects of methods of the present invention and are characterized by effective delivery of QQ-modified reprogramming proteins via the enhanced permeability and retention effect (EPR effect) of the angiogenic blood vessels.
- EPR effect enhanced permeability and retention effect
- Conditions characterized by damaged, and/or defective cells treated according to the present disclosure are various human conditions, including, but not limited to, cancer; cardiovascular disease or injury such as acute and chronic myocardial infarction, ischemia, heart injury, coronary artery disease, congenital heart disease, cardiomyopathies such as alcoholic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, hypertensive cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, inflammatory cardiomyopathy, ischemic cardiomyopathy, cardiomyopathy secondary to a systemic metabolic disease, myocardiodystrophy, noncompaction cardiomyopathy, restrictive cardiomyopathy, and valvular cardiomyopathy; vascular disease or blood vessel damage; anemias; ischemic and hemorrhagic stroke; metabolic diseases or conditions, such as diabetes, type I and type II, and obesity; neurological diseases and injuries such as spinal cord injury, traumatic brain injury, Huntington's disease, schizophrenia, Alzheimer's disease, amyotrophic lateral sclerosis, ataxias, autism,
- the use is directed to a method of treating cancer.
- cancers treated by using methods and compositions described herein are characterized by abnormal cell proliferation including, but not limited to, pre-neoplastic hyperproliferation, cancer in-situ, neoplasms and metastasis.
- the terms "treating” and “treatment” used to refer to treatment of a cancer in a subject include: inhibiting or ameliorating the cancer in the subject, such as slowing progression of the cancer and/or reducing or ameliorating a sign or symptom of the cancer.
- a therapeutically effective amount of a composition including an anti-cancer composition of the present invention is an amount which has a beneficial effect in a subject being treated.
- a therapeutically effective amount of a QQ-modified protein is effective to ameliorate one or more signs and/or symptoms of the cancer.
- a therapeutically effective amount of a composition is effective to detectably decrease proliferation of cells of a cancer characterized by abnormal cell proliferation including, but not limited to, pre-neoplastic hyperproliferation, cancer in-situ, neoplasms, metastasis, a tumor, a benign growth or other condition responsive to an administered QQ-modified protein.
- Such cancers include solid and non-solid cancers such as cancer of the bladder; breast; colorectal; cervical; esophagus; head and neck; kidney; lung; cancers of the nervous system such as glioblastoma, astrocytoma, ependymoma, neuroblastoma, retinoblastoma, meningiomas, granular cell tumors and nerve sheath tumors; ovary; pancreas; prostate; skin; stomach; testicle; throat cancer; urachus; or vagina.
- solid and non-solid cancers such as cancer of the bladder; breast; colorectal; cervical; esophagus; head and neck; kidney; lung; cancers of the nervous system such as glioblastoma, astrocytoma, ependymoma, neuroblastoma, retinoblastoma, meningiomas, granular cell tumors and nerve sheath tumors; ovary; pan
- a pharmaceutical composition for use according to aspects of the present invention includes a QQ-modified reprogramming protein and a pharmaceutically acceptable carrier.
- pharmaceutically acceptable carrier refers to a carrier or diluent that is generally non-toxic to an intended recipient and which does not significantly inhibit activity of a QQ-modified protein or other active agent included in the composition.
- a composition for use according to the present invention generally includes about 0.1-99% of a QQ-modified reprogramming protein.
- compositions suitable for delivery to a subject may be prepared in various forms illustratively including physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
- compositions optionally include a buffer, a solvent, or a diluent.
- aqueous and nonaqueous carriers examples include water, ethanol, polyols such as propylene glycol, polyethylene glycol and glycerol; vegetable oils such as olive oil; and injectable organic esters such as ethyloleate; and suitable mixtures of any two or more thereof.
- Such formulations are administered by a suitable route including parenteral administration.
- administration includes systemic or local administration.
- compositions may also contain adjuvants such as preserving, wetting, emulsifying, and dispensing agents. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like.
- One or more isotonic agents is optionally included, for example, sugars and/or salts such as sodium chloride.
- QQ-modified proteins are administered by topical application.
- a topical formulation can be an ointment, lotion, cream or gel in particular aspects.
- Topical dosage forms such as ointment, lotion, cream or gel bases are e.g. described in Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott Williams & Wilkins, 2006, p.880-882 and p.886-888 ; and in Allen, L. V. et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems, 8th Ed., Lippincott Williams & Wilkins, 2005, p.277-297 .
- compositions are known in the art and are e.g. described in Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins, Philadelphia, PA, 2006 ; and Allen, L.V. et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems, 8th Ed., Lippincott, Williams & Wilkins, Philadelphia, PA, 2005 .
- a pharmaceutical composition including a QQ-modified protein is suitable for administration to a subject by a variety of systemic and/or local routes including, but not limited to, parenteral, oral, rectal, nasal, pulmonary, epidural, ocular, otic, intraarterial, intracardiac, intracerebroventricular, intracranial, intradermal, intravenous, intramuscular, intraperitoneal, intraosseous, intrathecal, intratumoral, intravesical, subcutaneous, topical, transdermal, and transmucosal, such as by sublingual, buccal, vaginal, and inhalational routes of administration.
- parenteral oral, rectal, nasal, pulmonary, epidural, ocular, otic, intraarterial, intracardiac, intracerebroventricular, intracranial, intradermal, intravenous, intramuscular, intraperitoneal, intraosseous, intrathecal, intratumoral, intravesical, subcutaneous, topical, transdermal, and transmucosal,
- a pharmaceutical composition for use according to the present invention may be administered acutely or chronically.
- a composition as described herein may be administered as a unitary dose or in multiple doses over a relatively limited period of time, such as seconds - hours.
- administration may include multiple doses administered over a period of days - years, such as for chronic treatment of cancer.
- a therapeutically effective amount of a QQ-modified protein will vary depending on the route of administration and form of the composition being administered and the particular composition administered, the severity and type of condition being treated in the subject, the species of the subject, the age and sex of the subject and the general physical characteristics of the subject to be treated.
- One of skill in the art could determine a therapeutically effective amount in view of these and other considerations typical in medical practice without undue experimentation in view of the present disclosure and what is known in the art.
- a therapeutically effective amount would be in the range of about 0.001 ng/kg - 100 mg/kg body weight, optionally in the range of about 0.01 ng/kg - 1 mg/kg, and further optionally in the range of about 0.1 ng/kg - 0.1 mg/kg. Further, dosage may be adjusted depending on whether treatment is to be acute or continuing.
- a QQ-modified protein can be administered twice a day, daily, biweekly, weekly, every other week, monthly or at some other interval, for a treatment course extending one day, 1 week, 2 weeks, 4 weeks, 1 month, 2 months, 3-6 months or longer.
- a course of treatment is optionally repeated and may extend to chronic treatment if necessary.
- Administration of a QQ-modified protein according to aspects of use in a method of the present invention includes administration according to a dosage regimen to produce a desired response.
- a suitable schedule for administration of doses depends on several factors including age, weight, gender, medical history and health status of the subject, type of composition used and route of administration, for example.
- One of skill in the art is able to readily determine a dose and schedule of administration for a particular subject.
- a QQ-modified protein as a pharmaceutical formulation
- routes of administration include, but are not limited to, parenteral, oral, rectal, nasal, pulmonary, epidural, ocular, otic, intraarterial, intracardiac, intracerebroventricular, intracranial, intradermal, intravenous, intramuscular, intraperitoneal, intraosseous, intrathecal, intratumoral, intravesical, subcutaneous, topical, transdermal, and transmucosal, such as by sublingual, buccal, vaginal, and inhalational routes of administration.
- the QQ-modified protein may be administered parenterally, for example, by injection such as intravenous injection, intramuscular injection, intraperitoneal injection, subcutaneous injection, transdermal injection, intrathecal injection, intracranial injection, intracerebrospinal injection, and/or continuous infusion such as by an intravenous or intracerebrospinal continuous infusion device.
- injection such as intravenous injection, intramuscular injection, intraperitoneal injection, subcutaneous injection, transdermal injection, intrathecal injection, intracranial injection, intracerebrospinal injection, and/or continuous infusion such as by an intravenous or intracerebrospinal continuous infusion device.
- a protein transduction reagent-modified reprogramming protein is a DNA binding transcription factor.
- Administration of a protein transduction reagent-modified reprogramming protein is effective to reprogram one or more cell types in situ at the site of disease or damage to treat the disease or damage in vivo according to aspects described herein.
- Administration of a protein transduction reagent-modified reprogramming protein is effective to reprogram one or more cell types in situ at the site of disease or damage, generating transient stem cells which then differentiate into normal cells in situ at the site of disease or damage in vivo to treat the disease or damage according to aspects described herein.
- Protein transduction reagent-modified Sox2, protein transduction reagent-modified Oct4 and protein transduction reagent-modified Nanog is/are used in methods of treating cancer according to aspects of the present invention including administering them.
- Two or more of: protein transduction reagent-modified Sox2, protein transduction reagent-modified Oct4 and protein transduction reagent-modified Nanog may be used in methods of treating cancer according to aspects of the present invention including administering them. Such methods produce new normal cells at the site of the cancer by reprogramming cancer cells at the site.
- protein transduction reagent-modified Sox2, protein transduction reagent-modified Oct4 and protein transduction reagent-modified Nanog may be used in methods of treating brain tumor according to aspects of the present invention including administering them.
- Two or more of: protein transduction reagent-modified Sox2, protein transduction reagent-modified Oct4 and protein transduction reagent-modified Nanog may be used in methods of treating brain tumor according to aspects of the present invention including administering them.
- Protein transduction reagent-modified Sox2, protein transduction reagent-modified Oct4 and protein transduction reagent-modified Nanog may be used in methods of treating brain tumor according to aspects of the present invention including administering them.
- Such methods produce new normal cells at the site of the brain tumor by reprogramming brain tumor cells at the site.
- Protein transduction reagent-modified Sox2 and, optionally, protein transduction reagent-modified NeuroD may be used in methods of treating brain tumor according to aspects of the present invention including administering them.
- Protein transduction reagent-modified Sox2, and, optionally, protein transduction reagent-modified NeuroD may be used in methods of treating pancreatic cancer according to aspects of the present invention including administering them. Such methods produce new normal cells at the site of pancreatic cancer by reprogramming pancreatic cancer cells at the site.
- protein transduction reagent-modified Sox2, protein transduction reagent-modified Oct4 and protein transduction reagent-modified Nanog may be used in methods of treating breast cancer according to aspects of the present invention including administering them.
- Two or more of: isolated protein transduction reagent-modified Sox2, protein transduction reagent-modified Oct4 and protein transduction reagent-modified Nanog may be used in methods of treating breast cancer according to aspects of the present invention including administering them.
- Protein transduction reagent-modified Sox2, protein transduction reagent-modified Oct4 and protein transduction reagent-modified Nanog may be used in methods of treating breast cancer according to aspects of the present invention including administering them.
- Such methods produce new normal cells at the site of the breast cancer by reprogramming breast cancer cells at the site.
- Methods of treating breast cancer including administering one or more of: protein transduction reagent-modified Sox9, protein transduction reagent-modified Slug, protein transduction reagent-modified Gata3, protein transduction reagent-modified Brca-1 and protein transduction reagent-modified State5a.
- Methods of treating breast cancer are disclosed including administering two or more of: protein transduction reagent-modified Sox9, protein transduction reagent-modified Slug, protein transduction reagent-modified Gata3, protein transduction reagent-modified Brca-1 and protein transduction reagent-modified State5a.
- Methods of treating breast cancer including administering three or more of: protein transduction reagent-modified Sox9, protein transduction reagent-modified Slug, protein transduction reagent-modified Gata3, protein transduction reagent-modified Brca-1 and protein transduction reagent-modified State5a.
- Methods of treating breast cancer are disclosed including administering four or more of: protein transduction reagent-modified Sox9, protein transduction reagent-modified Slug, protein transduction reagent-modified Gata3, protein transduction reagent-modified Brca-1 and protein transduction reagent-modified State5a.
- Methods of treating breast cancer including administering: protein transduction reagent-modified Sox9, protein transduction reagent-modified Slug, protein transduction reagent-modified Gata3, protein transduction reagent-modified Brca-1 and protein transduction reagent-modified State5a.
- Such methods produce new normal cells at the site of breast cancer by reprogramming breast cancer cells at the site.
- Protein transduction reagent-modified Sox2, protein transduction reagent-modified Oct4 and protein transduction reagent-modified Nanog may be used in methods of treating pancreatic cancer according to aspects of the present invention including administering them.
- Two or more of: Protein transduction reagent-modified Sox2, protein transduction reagent-modified Oct4 and protein transduction reagent-modified Nanog may be used in methods of treating pancreatic cancer according to aspects of the present invention including administering them.
- Protein transduction reagent-modified Sox2, protein transduction reagent-modified Oct4 and protein transduction reagent-modified Nanog may be used in methods of treating pancreatic cancer according to aspects of the present invention including administering them.
- Such methods produce new normal cells at the site of pancreatic cancer by reprogramming pancreatic cancer cells at the site.
- Methods of treating pancreatic cancer including administering one or more of: protein transduction reagent-modified PDX1, protein transduction reagent-modified PAX4, protein transduction reagent-modified MafA and protein transduction reagent-modified Ngn3.
- Methods of treating pancreatic cancer are disclosed including administering two or more of: protein transduction reagent-modified PDX1, protein transduction reagent-modified PAX4, protein transduction reagent-modified MafA and protein transduction reagent-modified Ngn3.
- Methods of treating pancreatic cancer including administering three or more of: protein transduction reagent-modified PDX1, protein transduction reagent-modified PAX4, protein transduction reagent-modified MafA and protein transduction reagent-modified Ngn3.
- Methods of treating pancreatic cancer are disclosed including administering: protein transduction reagent-modified PDX1, protein transduction reagent-modified PAX4, protein transduction reagent-modified MafA and protein transduction reagent-modified Ngn3.
- Such methods produce new normal cells at the site of pancreatic cancer by reprogramming pancreatic cancer cells at the site.
- Methods of treating a heart disease or heart damage include administering one or more of: protein transduction reagent-modified Gata4, protein transduction reagent-modified Hand2, protein transduction reagent-modified MEF2c and protein transduction reagent-modified Tbox5.
- Methods of treating a heart disease or heart damage are disclosed and include administering two or more of: protein transduction reagent-modified Gata4, protein transduction reagent-modified Hand2, protein transduction reagent-modified MEF2c and protein transduction reagent-modified Tbox5.
- Methods of treating a heart disease or heart damage include administering three or more of: protein transduction reagent-modified Gata4, protein transduction reagent-modified Hand2, protein transduction reagent-modified MEF2c and protein transduction reagent-modified Tbox5.
- Methods of treating a heart disease or heart damage are disclosed and include administering: protein transduction reagent-modified Gata4, protein transduction reagent-modified Hand2, protein transduction reagent-modified MEF2c and protein transduction reagent-modified Tbox5.
- Such methods produce new cardiomyocytes, smooth muscle cells and endothelial cells at the site of the disease or damage by reprogramming fibroblasts at the site.
- Such methods produce new hepatocytes at the site of the disease or damage by reprogramming fibroblasts at the site.
- liver disease or liver damage include familial hyper-cholesterolaemia (FH), Crigler-Najjar syndrome and hereditary tryosinaemica I.
- Methods of treating a liver disease or liver damage include administering one or more of: protein transduction reagent-modified Hnfla, protein transduction reagent-modified Foxal, protein transduction reagent-modified Foxa2 and protein transduction reagent-modified Foxa3.
- Methods of treating a liver disease or liver damage are disclosed and include administering two or more of: protein transduction reagent-modified Hnfla, protein transduction reagent-modified Foxal, protein transduction reagent-modified Foxa2 and protein transduction reagent-modified Foxa3.
- Methods of treating a liver disease or liver damage include administering: protein transduction reagent-modified Hnfla, protein transduction reagent-modified Foxal, protein transduction reagent-modified Foxa2 and protein transduction reagent-modified Foxa3.
- Such methods produce new hepatocytes at the site of the disease or damage by reprogramming fibroblasts at the site.
- Examples of such liver disease or liver damage include familial hyper-cholesterolaemia (FH), Crigler-Najjar syndrome and hereditary tryosinaemica I.
- Methods of treating atherosclerosis include administering one or more of: protein transduction reagent-modified CEBP/ ⁇ / ⁇ and protein transduction reagent-modified PU.1.
- Methods of treating atherosclerosis are disclosed and include administering both of: CEBP/ ⁇ / ⁇ and protein transduction reagent-modified PU.1.
- Such methods produce new foam cells and macrophages at the site of the atherosclosis by reprogramming fibroblasts at the site.
- Methods of treating a neurodegenerative disease or neuronal tissue damage include administering one or more of: protein transduction reagent-modified Brn2, protein transduction reagent-modified Sox2 and protein transduction reagent-modified Foxg1.
- Methods of treating a neurodegenerative disease or neuronal tissue damage are disclosed and include administering two or more of: protein transduction reagent-modified Brn2, protein transduction reagent-modified Sox2 and protein transduction reagent-modified Foxg1.
- Methods of treating neurodegenerative disease or neuronal tissue damage are disclosed and include administering: protein transduction reagent-modified Brn2, protein transduction reagent-modified Sox2 and protein transduction reagent-modified Foxg1.
- Such methods produce new neurons at the site of the disease or damage by reprogramming fibroblasts at the site.
- Methods of treating a neurodegenerative disease or neuronal tissue damage include administering one or more of: protein transduction reagent-modified Asc1, protein transduction reagent-modified Lmxla, protein transduction reagent-modified Nurr1, protein transduction reagent-modified Brn2 and protein transduction reagent-modified Mytll.
- Methods of treating neurodegenerative disease or neuronal tissue damage are disclosed and include administering two or more of: protein transduction reagent-modified Asc1, protein transduction reagent-modified Lmxla, protein transduction reagent-modified Nurr1, protein transduction reagent-modified Brn2 and protein transduction reagent-modified Mytll.
- Methods of treating neurodegenerative disease or neuronal tissue damage include administering three or more of: protein transduction reagent-modified Asc1, protein transduction reagent-modified Lmxla, protein transduction reagent-modified Nurr1, protein transduction reagent-modified Brn2 and protein transduction reagent-modified Mytll.
- Methods of treating neurodegenerative disease or neuronal tissue damage are disclosed and include administering four or more of: protein transduction reagent-modified Asc1, protein transduction reagent-modified Lmx1a, protein transduction reagent-modified Nurr1, protein transduction reagent-modified Brn2 and protein transduction reagent-modified Mytll.
- Methods of treating neurodegenerative disease or neuronal tissue damage include administering: protein transduction reagent-modified Asc1, protein transduction reagent-modified Lmxla, protein transduction reagent-modified Nurr1, protein transduction reagent-modified Brn2 and protein transduction reagent-modified Mytll.
- Such methods produce new glutamatergic neurons at the site of the disease or damage by reprogramming fibroblasts at the site.
- Methods of treating a neurodegenerative disease or neuronal tissue damage include administering one or more of: protein transduction reagent-modified Asc1, protein transduction reagent-modified Brn2, protein transduction reagent-modified Mytll and protein transduction reagent-modified NeuroD1.
- Methods of treating neurodegenerative disease or neuronal tissue damage are disclosed and include administering two or more of: protein transduction reagent-modified Asc1, protein transduction reagent-modified Brn2, protein transduction reagent-modified Mytll and protein transduction reagent-modified NeuroD1.
- Methods of treating neurodegenerative disease or neuronal tissue damage include administering three or more of: protein transduction reagent-modified Asc1, protein transduction reagent-modified Brn2, protein transduction reagent-modified Mytll and protein transduction reagent-modified NeuroD1.
- Methods of treating neurodegenerative disease or neuronal tissue damage are disclosed and include administering: protein transduction reagent-modified Asc1, protein transduction reagent-modified Brn2, protein transduction reagent-modified Mytll and protein transduction reagent-modified NeuroD1.
- Such methods produce new glutamatergic neurons at the site of the disease or damage by reprogramming fibroblasts at the site.
- Methods of treating a neurodegenerative disease or neuronal tissue damage include administering: protein transduction reagent-modified Ngn2. Such methods produce new glutamatergic neurons at the site of the disease or damage by reprogramming astrocytes at the site.
- Methods of treating a neurodegenerative disease or neuronal tissue damage include administering one or more of: protein transduction reagent-modified Sox2 and protein transduction reagent-modified NeuroD1.
- Methods of treating neurodegenerative disease or neuronal tissue damage are disclosed and include administering: protein transduction reagent-modified Sox2 and protein transduction reagent-modified NeuroD1.
- Such methods produce new neural stem cells at the site of the disease or damage.
- Methods of treating a neurological disease or neuronal tissue damage include administering one or more of: protein transduction reagent-modified Brn2, protein transduction reagent-modified Ascl1, protein transduction reagent-modified Mytll, protein transduction reagent-modified Lhx3 and protein transduction reagent-modified Hb9.
- Methods of treating neurological disease or neuronal tissue damage are disclosed and include administering two or more of: protein transduction reagent-modified Brn2, protein transduction reagent-modified Ascl1, protein transduction reagent-modified Mytll, protein transduction reagent-modified Lhx3 and protein transduction reagent-modified Hb9.
- Methods of treating neurological disease or neuronal tissue damage include administering three or more of: protein transduction reagent-modified Brn2, protein transduction reagent-modified Ascl1, protein transduction reagent-modified Mytll, protein transduction reagent-modified Lhx3 and protein transduction reagent-modified Hb9.
- Methods of treating neurological disease or neuronal tissue damage are disclosed and include administering four or more of: protein transduction reagent-modified Brn2, protein transduction reagent-modified Ascl1, protein transduction reagent-modified Mytll, protein transduction reagent-modified Lhx3 and protein transduction reagent-modified Hb9.
- Methods of treating neurological disease or neuronal tissue damage include administering: protein transduction reagent-modified Brn2, protein transduction reagent-modified Ascl1, protein transduction reagent-modified Mytll, protein transduction reagent-modified Lhx3 and protein transduction reagent-modified Hb9.
- Such methods produce new motor neurons at the site of the disease or damage by reprogramming fibroblasts at the site.
- neurological diseases include amyotrophic lateral sclerosis (ALS).
- Methods of treating a neurological disease or neuronal tissue damage include administering one or more of: protein transduction reagent-modified Brn2, protein transduction reagent-modified Ascl1, protein transduction reagent-modified Mytll, protein transduction reagent-modified Lhx3, protein transduction reagent-modified Hb9, protein transduction reagent-modified Lsll and protein transduction reagent-modified Ngn2.
- Methods of treating neurological disease or neuronal tissue damage include administering two or more of: protein transduction reagent-modified Brn2, protein transduction reagent-modified Ascl1, protein transduction reagent-modified Mytll, protein transduction reagent-modified Lhx3, protein transduction reagent-modified Hb9, protein transduction reagent-modified Lsl1 and protein transduction reagent-modified Ngn2.
- Methods of treating neurological disease or neuronal tissue damage include administering three or more of: protein transduction reagent-modified Brn2, protein transduction reagent-modified Ascl1, protein transduction reagent-modified Mytll, protein transduction reagent-modified Lhx3, protein transduction reagent-modified Hb9, protein transduction reagent-modified Lsll and protein transduction reagent-modified Ngn2.
- Methods of treating neurological disease or neuronal tissue damage include administering four or more of: protein transduction reagent-modified Brn2, protein transduction reagent-modified Ascl1, protein transduction reagent-modified Mytll, protein transduction reagent-modified Lhx3, protein transduction reagent-modified Hb9, protein transduction reagent-modified Lsll and protein transduction reagent-modified Ngn2.
- Methods of treating neurological disease or neuronal tissue damage include administering five or more of: protein transduction reagent-modified Brn2, protein transduction reagent-modified Ascl1, protein transduction reagent-modified Mytll, protein transduction reagent-modified Lhx3, protein transduction reagent-modified Hb9, protein transduction reagent-modified Lsll and protein transduction reagent-modified Ngn2.
- Methods of treating neurological disease or neuronal tissue damage include administering six or more of: protein transduction reagent-modified Brn2, protein transduction reagent-modified Ascl1, protein transduction reagent-modified Mytll, protein transduction reagent-modified Lhx3, protein transduction reagent-modified Hb9, protein transduction reagent-modified Lsll and protein transduction reagent-modified Ngn2.
- Methods of treating neurological disease or neuronal tissue damage include administering: protein transduction reagent-modified Brn2, protein transduction reagent-modified Ascl1, protein transduction reagent-modified Mytll, protein transduction reagent-modified Lhx3, protein transduction reagent-modified Hb9, protein transduction reagent-modified Lsll and protein transduction reagent-modified Ngn2.
- Such methods produce new motor neurons at the site of the disease or damage by reprogramming fibroblasts at the site. Examples of such neurological diseases include amyotrophic lateral sclerosis (ALS).
- ALS amyotrophic lateral sclerosis
- Methods of treating a neurological disease or neuronal tissue damage include administering: protein transduction reagent-modified Dlx2. Such methods produce new GABA neurons at the site of the disease or damage by reprogramming fibroblasts at the site.
- neurological diseases include amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA) and Parkinson's disease.
- Methods of treating a neurological disease or neuronal tissue damage include administering: protein transduction reagent-modified Dlx2 and protein transduction reagent-modified Ascl1.
- Such methods produce new GABA neurons at the site of the disease or damage by reprogramming astrocytes at the site.
- Examples of such neurological diseases include spinal muscular atrophy (SMA).
- Methods of treating a neurological disease or neuronal tissue damage include administering one or more of: protein transduction reagent-modified Asc1, protein transduction reagent-modified Brn2, protein transduction reagent-modified Mytll, protein transduction reagent-modified Lmxla and protein transduction reagent-modified Foxa2.
- Methods of treating neurological disease or neuronal tissue damage are disclosed and include administering two or more of: protein transduction reagent-modified Asc1, protein transduction reagent-modified Brn2, protein transduction reagent-modified Mytll, protein transduction reagent-modified Lmxla and protein transduction reagent-modified Foxa2.
- Methods of treating neurological disease or neuronal tissue damage include administering three or more of: protein transduction reagent-modified Asc1, protein transduction reagent-modified Brn2, protein transduction reagent-modified Mytll, protein transduction reagent-modified Lmxla and protein transduction reagent-modified Foxa2.
- Methods of treating neurological disease or neuronal tissue damage are disclosed and include administering four or more of: protein transduction reagent-modified Asc1, protein transduction reagent-modified Brn2, protein transduction reagent-modified Mytll, protein transduction reagent-modified Lmxla and protein transduction reagent-modified Foxa2.
- Methods of treating neurological disease or neuronal tissue damage include administering: protein transduction reagent-modified Asc1, protein transduction reagent-modified Brn2, protein transduction reagent-modified Mytll, protein transduction reagent-modified Lmxla and protein transduction reagent-modified Foxa2.
- Such methods produce new dopamine neurons at the site of the disease or damage by reprogramming fibroblasts at the site. Examples of such neurological diseases include Parkinson's disease.
- Methods of treating a neurological disease or neuronal tissue damage include administering one or more of: protein transduction reagent-modified Asc1, protein transduction reagent-modified Lmxla and protein transduction reagent-modified Nurr1.
- Methods of treating a neurological disease or neuronal tissue damage are disclosed and include administering two or more of: protein transduction reagent-modified Asc1, protein transduction reagent-modified Lmxla and protein transduction reagent-modified Nurr1.
- Methods of treating neurological disease or neuronal tissue damage are disclosed and include administering: protein transduction reagent-modified Asc1, protein transduction reagent-modified Lmxla and protein transduction reagent-modified Nurr1.
- Such methods produce new neurons at the site of the disease or damage by reprogramming fibroblasts at the site. Examples of such neurological diseases include Parkinson's disease.
- Methods of treating a disease or disorder of the blood include administering: protein transduction reagent-modified Oct4. Such methods produce new hematopoietic cells at the site of the disease or damage by reprogramming fibroblasts at the site.
- Methods of treating diabetes, a pancreatic disease or pancreatic tissue damage include administering one or more of: protein transduction reagent-modified Ngn3, protein transduction reagent-modified Pdxl and protein transduction reagent-modified Pax4.
- Methods of treating diabetes, a pancreatic disease or pancreatic tissue damage are disclosed and include administering two or more of: protein transduction reagent-modified Ngn3, protein transduction reagent-modified Pdxl and protein transduction reagent-modified Pax4.
- Methods of treating diabetes, a pancreatic disease or pancreatic tissue damage include administering: protein transduction reagent-modified Ngn3, protein transduction reagent-modified Pdxl and protein transduction reagent-modified Pax4. Such methods produce new pancreatic beta-cells at the site of the disease or damage by reprogramming fibroblasts at the site.
- Methods of treating diabetes, a pancreatic disease or pancreatic tissue damage include administering one or more of: protein transduction reagent-modified Ngn3, protein transduction reagent-modified Pdxl and protein transduction reagent-modified MafA.
- Methods of treating diabetes, a pancreatic disease or pancreatic tissue damage are disclosed and include administering two or more of: protein transduction reagent-modified Ngn3, protein transduction reagent-modified Pdxl and protein transduction reagent-modified MafA.
- Methods of treating diabetes, a pancreatic disease or pancreatic tissue damage include administering: protein transduction reagent-modified Ngn3, protein transduction reagent-modified Pdxl and protein transduction reagent-modified MafA. Such methods produce new pancreatic beta-cells at the site of the disease or damage by reprogramming pancreatic exocrine cells at the site.
- Methods of treating obesity include administering one or both of: protein transduction reagent-modified Prdm16 and protein transduction reagent-modified C/EBPb.
- Methods of treating obesity are disclosed and include administering both: protein transduction reagent-modified Prdm16 and protein transduction reagent-modified C/EBPb.
- Such methods produce new brown adipocytes at the site of the disease or damage by reprogramming white adipocytes at the site.
- Methods of treating a muscle disease or muscle damage include administering: protein transduction reagent-modified MyoD. Such methods produce new muscle cells at the site of the disease or damage by reprogramming fibroblasts at the site.
- Methods of treating arthritis, osteoarthritis, cartilage degeneration and/or cartilage injury include administering one or more of: protein transduction reagent-modified Sox9, protein transduction reagent-modified Runx2, protein transduction reagent-modified Sox5 and protein transduction reagent-modified Sox6.
- Methods of treating arthritis, osteoarthritis, cartilage degeneration and/or cartilage injury are disclosed and include administering two or more of: protein transduction reagent-modified Sox9, protein transduction reagent-modified Runx2, protein transduction reagent-modified Sox5 and protein transduction reagent-modified Sox6.
- Methods of treating arthritis, osteoarthritis, cartilage degeneration and/or cartilage injury include administering three or more of: protein transduction reagent-modified Sox9, protein transduction reagent-modified Runx2, protein transduction reagent-modified Sox5 and protein transduction reagent-modified Sox6.
- Methods of treating arthritis, osteoarthritis, cartilage degeneration and/or cartilage injury are disclosed and include administering: protein transduction reagent-modified Sox9, protein transduction reagent-modified Runx2, protein transduction reagent-modified Sox5 and protein transduction reagent-modified Sox6.
- Such methods produce new chondrocytes at the site of the disease or damage by reprogramming fibroblasts at the site.
- Methods of treating a breast disease or breast tissue damage include administering one or more of: protein transduction reagent-modified Sox9, protein transduction reagent-modified Slug, protein transduction reagent-modified Stat5a, protein transduction reagent-modified Gata3 and protein transduction reagent-modified Brca-1.
- Methods of treating a breast disease or breast tissue damage are disclosed and include administering protein transduction reagent-modified Brca-1.
- Methods of treating a breast disease or breast tissue damage include administering two or more of: protein transduction reagent-modified Sox9, protein transduction reagent-modified Slug, protein transduction reagent-modified Stat5a, protein transduction reagent-modified Gata3 and protein transduction reagent-modified Brca-1.
- Methods of treating a breast disease or breast tissue damage are disclosed and include administering both: protein transduction reagent-modified Sox9 and protein transduction reagent-modified Slug.
- Methods of treating a breast disease or breast tissue damage are disclosed and include administering both: protein transduction reagent-modified Stat5a and protein transduction reagent-modified Gata3.
- Methods of treating a breast disease or breast tissue damage include administering three or more of: protein transduction reagent-modified Sox9, protein transduction reagent-modified Slug, protein transduction reagent-modified Stat5a, protein transduction reagent-modified Gata3 and protein transduction reagent-modified Brca-1.
- Methods of treating a breast disease or breast tissue damage are disclosed and include administering four or more of: protein transduction reagent-modified Sox9, protein transduction reagent-modified Slug, protein transduction reagent-modified Stat5a, protein transduction reagent-modified Gata3 and protein transduction reagent-modified Brca-1.
- Methods of treating a breast disease or breast tissue damage include administering: protein transduction reagent-modified Sox9, protein transduction reagent-modified Slug, protein transduction reagent-modified Stat5a, protein transduction reagent-modified Gata3 and protein transduction reagent-modified Brca-1.
- Such methods produce new mammary duct cells at the site of the disease or damage by reprogramming fibroblasts at the site.
- Methods of treating a vascular disease or blood vessel damage include administering one or more of: protein transduction reagent-modified Erg1, protein transduction reagent-modified Er71, protein transduction reagent-modified Fli1 and protein transduction reagent-modified Gata2.
- Methods of treating a vascular disease or blood vessel damage are disclosed and include administering two or more of: protein transduction reagent-modified Erg1, protein transduction reagent-modified Er71, protein transduction reagent-modified Fli1 and protein transduction reagent-modified Gata2.
- Methods of treating a vascular disease or blood vessel damage include administering three or more of: protein transduction reagent-modified Erg1, protein transduction reagent-modified Er71, protein transduction reagent-modified Fli1 and protein transduction reagent-modified Gata2.
- Methods of treating a vascular disease or blood vessel damage are disclosed and include administering: protein transduction reagent-modified Erg1, protein transduction reagent-modified Er71, protein transduction reagent-modified Fli1 and protein transduction reagent-modified Gata2.
- Such methods produce new endothelial cells at the site of the disease or damage by reprogramming cells at the site.
- Methods of treating a vascular disease or blood vessel damage include administering one or more of: protein transduction reagent-modified Hey1, protein transduction reagent-modified Hey2, protein transduction reagent-modified FoxC1 and protein transduction reagent-modified FoxC2.
- Methods of treating a vascular disease or blood vessel damage are disclosed and include administering two or more of: protein transduction reagent-modified Hey1, protein transduction reagent-modified Hey2, protein transduction reagent-modified FoxC1 and protein transduction reagent-modified FoxC2.
- Methods of treating a vascular disease or blood vessel damage include administering three or more of: protein transduction reagent-modified Hey1, protein transduction reagent-modified Hey2, protein transduction reagent-modified FoxC1 and protein transduction reagent-modified FoxC2.
- Methods of treating a vascular disease or blood vessel damage are disclosed and include administering: protein transduction reagent-modified Hey1, protein transduction reagent-modified Hey2, protein transduction reagent-modified FoxC1 and protein transduction reagent-modified FoxC2.
- Such methods produce new arterial endothelial cells at the site of the disease or damage by reprogramming cells at the site.
- Methods of treating a vascular disease or blood vessel damage include administering one or both of: protein transduction reagent-modified Sox7 and protein transduction reagent-modified Sox18.
- Methods of treating a vascular disease or blood vessel damage are disclosed and include administering both: protein transduction reagent-modified Sox7 and protein transduction reagent-modified Sox18.
- Such methods produce new venous endothelial cells at the site of the disease or damage by reprogramming cells at the site.
- Combinations of therapeutic agents are administered according to aspects of the present invention.
- At least one QQ-modified protein to be administered is selected from the group consisting of Sox2, Oct4 and Nanog.
- two or more isolated QQ-modified proteins are administered to a subject to for use in treating cancer in a subject in need thereof.
- At least one isolated QQ-modified protein and at least one additional therapeutic agent are administered to a subject for use in treating cancer in a subject in need thereof.
- At least one isolated QQ-modified protein and at least two additional therapeutic agents are administered to a subject for use in treating cancer in a subject in need thereof.
- two or more isolated QQ-modified proteins are administered to a subject for use in treating cancer in a subject in need thereof.
- at least one isolated QQ-modified protein and at least one additional therapeutic agent are administered to a subject for use in treating cancer in a subject in need thereof.
- at least one isolated QQ-modified protein and at least two additional therapeutic agents are administered to a subject for use in treating cancer in a subject in need thereof.
- additional therapeutic agent is used herein to denote a chemical compound, a mixture of chemical compounds, a biological macromolecule (such as a nucleic acid, an antibody, a protein or portion thereof, e.g., a peptide), or an extract made from biological materials such as bacteria, plants, fungi, or animal (particularly mammalian) cells or tissues which is a biologically, physiologically, or pharmacologically active substance (or substances) that acts locally or systemically in a subject.
- a biological macromolecule such as a nucleic acid, an antibody, a protein or portion thereof, e.g., a peptide
- an extract made from biological materials such as bacteria, plants, fungi, or animal (particularly mammalian) cells or tissues which is a biologically, physiologically, or pharmacologically active substance (or substances) that acts locally or systemically in a subject.
- Additional therapeutic agents included in aspects of methods and compositions of the present invention include, but are not limited to, antibiotics, antivirals, antineoplastic agents, analgesics, antipyretics, antidepressants, antipsychotics, anti-cancer agents, antihistamines, antiosteoporosis agents, anti-osteonecrosis agents, antiinflammatory agents, anxiolytics, chemotherapeutic agents, diuretics, growth factors, hormones, non-steroidal anti-inflammatory agents, steroids and vasoactive agents.
- Combination therapies utilizing one or more isolated QQ-modified proteins and one or more additional therapeutic agents may show synergistic effects, e.g., a greater therapeutic effect than would be observed using either the one or more isolated QQ-modified proteins or one or more additional therapeutic agents alone as a monotherapy.
- combination therapies include: (1) pharmaceutical compositions that include one or more QQ-modified proteins in combination with one or more additional therapeutic agents; and (2) co-administration of one or more isolated QQ-modified proteins with one or more additional therapeutic agents wherein the one or more isolated QQ-modified proteins and the one or more additional therapeutic agents have not been formulated in the same composition.
- the one or more isolated QQ-modified proteins may be administered at the same time, intermittent times, staggered times, prior to, subsequent to, or combinations thereof, with reference to the administration of the one or more additional therapeutic agents.
- Combination treatments can allow for reduced effective dosage and increased therapeutic index of the one or more isolated QQ-modified proteins and the one or more additional therapeutic agents used in methods of the present invention.
- a method of treating a subject having cancer or at risk of having cancer further includes an adjunct anti-cancer treatment.
- An adjunct anti-cancer treatment can be administration of an anti-cancer agent.
- Anti-cancer agents are described, for example, in Goodman et al., Goodman and Gilman's The Pharmacological Basis of Therapeutics, 8th Ed., Macmillan Publishing Co., 1990 .
- Anti-cancer agents illustratively include acivicin, aclarubicin, acodazole, acronine, adozelesin, aldesleukin, alitretinoin, allopurinol, altretamine, ambomycin, ametantrone, amifostine, aminoglutethimide, amsacrine, anastrozole, anthramycin, arsenic trioxide, asparaginase, asperlin, azacitidine, azetepa, azotomycin, batimastat, benzodepa, bicalutamide, bisantrene, bisnafide dimesylate, bizelesin, bleomycin, brequinar, bropirimine, busulfan, cactinomycin, calusterone, capecitabine, caracemide, carbetimer, carboplatin, carmustine, carubicin, carzelesin, cedef
- An adjunct anti-cancer treatment can be a radiation treatment of a subject or an affected area of a subject's body.
- DNA encoding each of Oct4, Sox2, Klf4, and c-Myc, Nanog, GATA4, Hand2, Mef2c and Tbox5 reprogramming proteins were separately subcloned into an sHT-pET30a bacterial expression vector, in which a short his-tag: 'HHHHHHSS' (SEQ ID NO:64) replaced the long his-tag in the pET30a expression vector from Novagen.
- a factor Xa (IEGR) cleavage site is placed between the short his-tag and the coding genes. The sequences of the bacterial expression vectors were confirmed by DNA sequencing.
- the DNA constructs of reprogramming proteins were transformed into E.Coli strain BL-21(DE3) or ClearColiTM BL21(DE3) bacterial cells individually.
- the ClearColiTM BL21(DE3) bacterial cells were used for production of recombinant reprogramming proteins which are endotoxin-free. A single colony was selected for bacterial protein expression. After brief optimization, protein expression was induced by 0.5-1.2 mM IPTG depending on different proteins and continued to culture at 18 C° for 12-16 hours. The cells were harvested in the binding buffer containing 6M urea and sonicated several times to extract proteins. The recombinant reprogramming proteins were purified using a His-Bind Resin column (Novagen) according to the manual with modifications.
- the protein extraction supernatant was loaded on the column twice, washed with 5 x column volume of the binding buffers.
- an additional washing step can be added during protein purification stage using 10 column volume of 0.2% of Triton X-114 to remove endotoxin from bacterially expressed recombinant reprogramming proteins.
- the column loaded with recombinant proteins is washed again using 10 x column volume washing buffer containing 15-50 mM imidazole.
- the purified proteins were eluted from the column using elusion buffer containing 500 mM imidazole.
- the purified proteins were dialyzed extensively against water and lyophilized into protein powders.
- QQ-modification Modification of expressed reprogramming proteins with protein transduction reagent to produce protein transduction reagent-modified reprogramming proteins
- the protein transduction reagent can be adjusted by altering the composition to include reagents as shown in Table 1 to obtain the best protein transduction efficiency for the particular reprogramming protein and cell type.
- the reprogramming protein(s) is first dissolved in sodium phosphate buffer (pH7.0, NaCl 50 mM) at concentrations of 0.5-10 mg/ml, depending on protein solubility. Protein solubility was found to influence cationization efficiency. To completely dissolve proteins, an overnight stir of the protein solution at room temperature is performed (with or without DTT at 3 mM for overnight, depending on if the reprogramming protein has cysteine residues). Proteins can also be dissolved in 1-6 M urea to improve protein solubility.
- the other ingredients of the QQ reagents (not including the lipid emulsion or the optional Ca or DMSO) were mixed in a tube, according to the recipe described above.
- the QQ reagent is then titrated into the protein solution very slowly, drop by drop, while stirring and then add the lipid emulsion. Once this is completed, the resulting protein solution is left at room temperature for 4 hours before use. During this period, gentle stirring is necessary to mix the QQ reagent with protein solution and also to allow the protein modification reaction to complete. If precipitation is observed, the protein solution can be centrifuged at 14,000 rpm for 15 minutes to remove the precipitate. If the precipitate occurs, a BCA protein assay will be carried out using the supernatant to check the amount of protein remaining in solution. To ensure the efficiency of protein transfer into the cells, the concentration of modified protein has to be high enough at >0.1 mg/ml.
- QQ-modified proteins are prepared at 0.5-1.5 mg/ml concentration, depending on protein solubility, for in vivo administration.
- QQ modification may be performed on each protein individually or on a mixture of proteins to be administered together to a subject.
- the QQ modification is performed on each protein individually, the QQ-modified proteins mixed together for several hours and then aliquoted into small tubes at 1ml/tube and stored at -20°C where they are stable for several months.
- QQ reagent can be used for protein modification.
- the QQ series reagents cover a wide range of cationization reagents along with different lipids and enhancers, thus any precipitation problem is solved. The above procedure can be repeated to prepare higher concentrations of protein transduction reagent-modified reprogramming protein.
- the protein transduction reagent-modified reprogramming protein is passed through a desalting column to separate the protein transduction reagent-modified reprogramming protein from remaining unreacted materials.
- the purified proteins are passed through a filter (0.22 ⁇ m cutoff, for sterilization before in vivo administration.
- the purified protein fractions can be concentrated before or after sterilization, such as by using a spin column, and are stable and can be stored at -20°C for between a few weeks to a few months.
- QQ reagents can also be used for the best efficiency of protein transfer as well as the least cell toxicity.
- different proteins are modified with different QQ reagents for best efficiency of protein transfer into cells.
- QQ5a-QQ9a are used for better in vivo delivery efficiency. However, this may cause larger in vivo toxicity.
- QQ5a-QQ9a use of lower concentrations of larger PEI and lipids is emphasized.
- QQ1a-QQ4a is used with less in vivo toxicity.
- QQ1-QQ4 can be used with higher lipid concentrations.
- the reprogramming proteins were dissolved in 50 mM sodium phosphate pH 7.4 with 2 M urea. Protein transduction reagents (QQ-reagents) were freshly prepared based on the recipe.
- QQ-reagent used in this example is a cocktail of polyethylenimine (PEI) 1,200 (1.2K, 0.05-1.0 mg/ml) and DOTAP/DOPE (25-100 ⁇ g/ml).
- PEI polyethylenimine
- DOTAP/DOPE 25-100 ⁇ g/ml.
- the QQ-modification of reprogramming proteins was performed by mixing the QQ-reagent with one or more reprogramming proteins, such as Oct4/Sox2/Nanog: 1 mg/ml, for 4-hours at room temperature or overnight in a cold room.
- Ferritin is a ubiquitous iron-containing protein useful as a negative contrast reagent for magnetic resonance imaging (MRI).
- ferritin or ferritin treated with QQ reagent to produce QQ-ferritin is intravenously injected into rats having brain tumors generated by implantation of rat gliosarcoma cell line 9L cells.
- rat gliosarcoma cell line 9L were freshly prepared and adjusted to 1x10 6 cells/ml before implantation.
- the intracranial xenografts were performed according to standard protocols. Fisher rats were anesthetized and placed in a stereotactic frame, and the skull was exposed. A hole was made 3 mm to the right and 1 mm anterior of the bregma, and 9L cells (5 x 10 4 cells in 5 ⁇ l) were injected using a 10- ⁇ l Hamilton syringe with a 26s-gauge needle mounted in a stereotactic holder (Bonaduz, GR, Switzerland).
- the syringe was lowered to a depth of 3.5 mm and then raised to a depth of 3.0 mm.
- the tumor cells were injected at a rate of 0.5 ⁇ l/10 s, and the craniotomy covered with Horsley's bone wax. 12-days after 9L-cell implantation, QQ-modified ferritin or ferritin alone, 100 ⁇ g/100 ⁇ l/rat, was injected via the rat tail vein.
- the rats were anesthetized and the rat brains were imaged by MRI. After MRI, the animals were sacrificed. The extracted brains were fixed in 4% paraformaldehyde overnight and then embedded in paraffin for further analysis.
- Six micrometer thin sections were cut from each of the blocks and were stained with hematoxylin and eosin. The sizes of brain tumors were microscopically determined.
- Figures 1A and 1B show MRI evidence of targeted delivery of QQ-ferritin into 9L-brain tumor in rats and no detectable ferritin in 9L-brain tumor of rats injected with ferritin alone.
- Figure 1A is a representative MRI image of a rat with 9L-brain tumor injected with QQ-ferritin via tail-vein. The arrow points to a 9L-brain tumor and the black color is indicative of ferritin delivered to the tumor.
- Figure 1B A representative MRI image of a rat with 9L-brain tumor injected with ferritin without QQ modification. No ferritin is observed in the brain tumor in this case although the rat was sacrificed and confirmed to have a large 9L-brain tumor.
- Double immunostains of the QQ-ferritin injected 9L-brain tumor tissue sections were performed using an antibody for a blood vessel marker, CD31, and an antibody for ferritin.
- the nuclei of the 9L-cancer cells in the sections were stained with DAPI.
- Overlapping immunostaining for the CD31 and ferritin were observed in blood vessels of the brain tumors, indicating that QQ-ferritin leaked out from the blood vessels by the enhanced permeability and retention effect (EPR effect) of the angiogenic blood vessels associated with brain tumor.
- EPR effect enhanced permeability and retention effect
- ferritin immunostaining in the 9L-tumor sections treated with ferritin without QQ-modification showed that the ferritin without QQ modification did not penetrate into tumor cells, although immunostaining indicated that this unmodified ferritin also leaked out of the tumor-associated angiogenic blood vessels.
- These unmodified ferritin nanoparticles were observed between cells and likely did not accumulate due to the fluid between cells inside the tissues so that no tumor was observed by MRI without QQ-modification of the ferritin.
- ferritin or ferritin treated with QQ reagent to produce QQ-ferritin is intravenously injected into mice having orthotopic breast tumors generated by implantation of mouse metastatic breast cancer cell line 4T1 cells.
- Implantation of mouse metastatic breast cancer cell line 4T1 cells in mice is a mouse model for spontaneous metastatic breast cancer.
- 4T1 cells were implanted into the breast (#4 fat pad) of 2 month old female BALB/c mice (20,000 4T1 cells in 50 ⁇ l/mouse). At day 18 after 4T1 cell implantation, 4T1 tumors had grown in the mouse breast to a size of ⁇ 1.0-1.5 cm in diameter.
- QQ-modified ferritin 100 ⁇ g/50 ⁇ l/mouse was injected via tail-vein. The mice were anesthetized and subjected to MRI imaging before injection of the QQ-modified ferritin and at 0.5 hours, 2 hours, 3.5 hours, 8 hours and 18 hours following the injection.
- Figures 2A-F are representative MRI images from this time course showing QQ-delivered ferritin in the primary tumor of breast cancer bearing mouse as darkened areas in the primary tumor. This primary tumor darkness was time-dependent and reached a maximum at 8-hours, then started to decrease in intensity.
- 4T1 cells (2 x 10 4 cells/50 ⁇ l/mouse) were implanted into female BALB/c mice. 15-days after tumor cell implantation Alexa Fluor594 labeled Klf4 was prepared. QQ-modified unlabeled Oct4 (QQ-Oct4) and QQ-modified Alexa Fluor594 labeled Klf4 were then prepared. Intra-tumoral injection of 50 ⁇ g QQ-Oct4 and QQ-Alexa Fluor594 labeled Klf4 proteins was performed. The mice were sacrificed 5 hours after injection and tumor tissue sections were prepared for immunostaining and fluorescence microscopy.
- Immunostaining for Oct4 in the primary 4T1-breast cancer tissue sections demonstrated nuclear localization of Oct4 in the 4T1-cancer cells and co-localization with DAPI.
- Fluorescence microscopic imaging also showed nuclear localization of Klf4 in the primary 4T1-breast cancer tissue sections and co-localization with DAPI.
- QQ-modified and fluorescence labeled GATA4, Sox2 and Oct4 are administered by an intraperitoneal injection to rats after myocardial infarction and the QQ-modified proteins and fluorescence label were delivered to injured heart tissues in the animals.
- GATA4, Sox2 and Oct4 are each labeled with Alexa Fluor488 according to methods specified by the manufacturer.
- the labeled GATA4, Sox2 and Oct4 proteins were purified with small spin columns.
- the Alexa Fluor488-GATA4, Alexa Fluor488-Sox2 and Alexa Fluor488-Oct4 are then QQ-modified to generate QQ-modified Alexa Fluor488-GATA4, QQ-modified Alexa Fluor488-Sox2 and QQ-modified Alexa Fluor488-Oct4.
- Lewis rats were anesthetized and coronary artery ligation surgery was performed to create myocardial infarction in the Lewis rats. 24-hours after coronary artery ligation surgery, QQ-modified Alexa Fluor488-labeled GATA4, QQ-modified Alexa Fluor488-labeled Sox2 and QQ-modified Alexa Fluor488-labeled Oct4 (200 ⁇ g/100 ⁇ l/rat) were intraperitoneally injected into Lewis rats.
- Fluorescence microscopic analysis showed colocalization of Alexa Fluor488-GATA4 protein with ⁇ -actinin immunofluorescence, indicating that intraperitoneal injection of QQfluorescence labeled GATA4 resulted in delivery of the GATA4 protein into the scar zone of the injured heart tissue after coronary artery ligation.
- fluorescence microscopic analysis of Alexa Fluor488-Sox2 and ⁇ -actinin immunofluorescence indicated that intraperitoneal injection of QQ- modified Alexa Fluor488 labeled-Sox2 resulted in location of the Sox2 protein in the border zone of the injured heart tissue after coronary artery ligation.
- glioma cells including 9L-, U251-, U87- and a primary GBM cell line from a patient were reprogrammed into protein induced pluripotent stem cells (piPSCs) using QQ-modified Sox2, Oct4 and Nanog (SON) proteins as follows: At day 0, glioma cells were seeded for 24-hours to allow them to grow in a 50 mm petri dish. At day 2, QQ-SON proteins were added to the culture medium at 0.5-2.0 ⁇ g/ml and cultured for 24 hours. Next day, fresh QQ-SON proteins were added into new culture medium and cultured for 24 hours. Such cycles were repeated for 5-7 cycles depending on glioma cells used for cell reprogramming.
- piPSCs protein induced pluripotent stem cells
- SON Nanog
- the culture media were changed to maintaining medium for 2 days.
- piPSC colonies appeared.
- whole dish passage was performed to expand the generated piPSCs.
- Immunostaining of the whole dish passaged glioma-piPSCs including both monolayer and colony of the 9L-piPSCs using pluripotency markers including nuclear markers Oct4, Nanog, Rex-1 and surface markers ALP, Tra1-60, and Tra1-81 showed nearly all cells were positive for these pluripotency markers.
- immunostains of 9L-cells showed negative stains for these markers.
- 4T1-piPSCs were generated from 4T1 mouse breast cancer cells.
- the reprogramming conversion efficiency of 4T1 cells into 4T1-piPSCs is 96 ⁇ 1.3% using the same whole well counting method (96-wells), see Table 3.
- Table 3 Conversion efficiency of QQ-SON protein-induced cell reprogramming of 4T1-breast cancer cells Pluripotent Marker Number of Wells Number of Colonies/Well Conversion Efficiency (%) Nanog 2 1344 ⁇ 200 98 ⁇ 1 Rex 1 2 1943 ⁇ 234 96 ⁇ 1 Sox 2 2 1862 ⁇ 198 94 ⁇ 2 Average 96 ⁇ 1.3
- Cells of human glioblastoma cell line U251 are reprogrammed into U251-piPSCs using QQ-modified Sox2, Oct4 and Nanog (SON) proteins as follows: At day 0, U251glioblastoma cells were seeded for 24-hours to allow them to grow in a 50 mm petri dish. At day 2, QQ-SON proteins were added to the culture medium at 0.5-2.0 ⁇ g/ml and cultured for 24 hours. Next day, fresh QQ-SON proteins were added into new culture medium and cultured for 24 hours. Such cycles were repeated for 5-7 cycles. At the end of cell reprogramming, the culture media were changed to maintaining medium for 2 days. During cell reprogramming, U251-piPSCs colonies appeared. At day 8, whole dish passage was performed to expand the generated U251-piPSCs.
- QQ-modified Sox2, Oct4 and Nanog SON proteins as follows: At day 0, U251glioblastoma cells were seeded
- FIG. 3A is a graph showing results of this assay indicating that cell reprogramming of glioma cells into piPSCs significantly reduces their proliferation, error Bar represents standard error of three independent experiments.
- GBM-piPSCs Cells of a patient-derived primary human glioblastoma multiforme (GBM) cell line, GBM (12-14), are reprogrammed into GBM-piPSCs using QQ-modified Sox2, Oct4 and Nanog (SON) proteins as follows: At day 0, GBM cells were seeded for 24-hours to allow them to grow in a 50 mm petri dish. At day 2, QQ-SON proteins were added to the culture medium at 0.5-2.0 ⁇ g/ml and cultured for 24 hours. Next day, fresh QQ-SON proteins were added into new culture medium and cultured for 24 hours. Such cycles were repeated for 5-7 cycles. At the end of cell reprogramming, the culture media were changed to maintaining medium for 2 days. During cell reprogramming, GBM1-piPSCs colonies appeared. At day 8, whole dish passage was performed to expand the generated GBM-piPSCs.
- QQ-modified Sox2, Oct4 and Nanog SON
- Dose-dependent chemotherapeutic drug sensitivity of patient-derived primary human GBM (12-14) cells (squares) and GBM (12-14)-piPSCs (circles) against the alkylating agent temozolomide was determined and results are shown in Figure 3B . Experiments were done in triplicate, mean ⁇ SD, p ⁇ 0.01. Drug sensitivity of the GBM-piPSCs was significantly enhanced to temozolomide as compared with the parental glioblastoma cells.
- Cells of rat gliosarcoma cell line 9L are reprogrammed into 9L-piPSCs using QQ-modified Sox2, Oct4 and Nanog (SON) proteins as follows: At day 0, 9L glioma cells were seeded for 24-hours to allow them to grow in a 50 mm petri dish. At day 2, QQ-SON proteins were added to the culture medium at 0.5-2.0 ⁇ g/ml and cultured for 24 hours. Next day, fresh QQ-SON proteins were added into new culture medium and cultured for 24 hours. Such cycles were repeated for 5-7 cycles. At the end of cell reprogramming, the culture media were changed to maintaining medium for 2 days. During cell reprogramming, 9L-piPSCs colonies appeared. At day 8, whole dish passage was performed to expand the generated 9L-piPSCs.
- QQ-modified Sox2, Oct4 and Nanog SON
- Dose-dependent chemotherapeutic drug sensitivity of 9L-cells (squares) and 9L-piPSCs (circles) against carboplatin was determined by an MTT assay and results are shown in Figure 3C . Experiments were done in triplicate, mean ⁇ SD, p ⁇ 0.01. Drug sensitivity of the 9L-piPSCs was significantly enhanced to carboplatin as compared with the parental 9L cells.
- Cells of mouse mammary tumor cell line 4T1 are reprogrammed into 4T1-piPSCs using QQ-modified Sox2, Oct4 and Nanog (SON) proteins as follows: At day 0, 4T1 cells were seeded for 24-hours to allow them to grow in a 50 mm petri dish. At day 2, QQ-SON proteins were added to the culture medium at 0.5-2.0 ⁇ g/ml and cultured for 24 hours. Next day, fresh QQ-SON proteins were added into new culture medium and cultured for 24 hours. Such cycles were repeated for 5-7 cycles. At the end of cell reprogramming, the culture media were changed to maintaining medium for 2 days. During cell reprogramming, 4T1-piPSCs colonies appeared. At day 8, whole dish passage was performed to expand the generated 4T1-piPSCs.
- QQ-modified Sox2, Oct4 and Nanog SON
- Proliferative activity of 4T1-cells and 4T1-piPSCs was assayed by determining the number of Ki67-positive cells and it was found that cell reprogramming of 4T1 mammary tumor cells into 4T1-piPSCs significantly reduces their proliferation.
- Dose-dependent chemotherapeutic drug sensitivity of 4T1-cells and 4T1-piPSCs against doxorubicin and paclitaxel was determined using an MTT assay. Drug sensitivity of the 4T1-piPSCs was significantly enhanced to doxorubicin and paclitaxel as compared with the parental 4T1 cells.
- Embryonic bodies were prepared for glioma-piPSCs using the hanging-drop method.
- the glioma-piPSCs EBs were placed into a spontaneous differentiation medium for 10-days, followed by immunostaining with markers of ectoderm, mesoderm and endoderm, showing positive immunostains of PAX6 for ectoderm, positive immunostains of desmin for mesoderm and positive immunostains of ⁇ -fetoprotein (AFP) for endoderm. Immunostaining of control 9L cells was negative for these markers. Similar results have been also obtained for 4T1-piPSCs, indicating that the 4T1-piPSCs also differentiated into three germ layers.
- Glioma-piPSCs EBs were placed into a specific neural-lineage inducing differentiation medium for 14-days, followed by immunostaining with neural lineage markers, showing positive immunostains of Tuj I for neurons, positive immunostains of GFAP for astrocytes and positive immunostains of nestin for neural stem cells. These neural-specifically differentiated cells also displayed neural cell morphology. Immunostaining of control 9L cells was negative for these markers.
- MET mesenchymal-to-epithelial transition
- results of Western blot analysis of several epithelial and mesenchymal markers of U251 cells and U251-piPSCs including E-cadherin (E-cad), ⁇ -catenin ( ⁇ -cat), vimentin (VMT), see Figure 4A , indicate an MET during cell reprogramming which is confirmed by cell morphology changes and qRT-PCR results.
- GFAP protein level is also significantly enhanced after cell reprogramming into U251-piPSCs from U251 cells, indicating that cell reprogramming caused a significant reduction of tumorigenicity of U251 cells in vitro during cell reprogramming. Actin protein expression was used as an internal control.
- 4T1-piPSCs also exhibited reduced proliferation, Figure 4D , reduced mammary sphere formation, Figure 4E , reduced migration, Figure 4F , and reduced invasion, Figure 4G , as compared to those properties of the parental 4T1 cells, indicating a significantly reduced tumorigenicity of 4T1 cells after cell reprogramming into 4T1-piPSCs in vitro.
- FIG. 5A is an image showing cell morphology of U251 cells
- Figure 5B is an image showing changes in cell morphology of U251 cells indirectly co-cultured with U251-piPSCs for 40-64 hours.
- a 2 nd co-culture is the indirect co-culture experiment that places the 1 st co-cultured cells into the transwell insert and fresh U251 cells in the basolateral chamber. Double immunostains of the U251 cells and indirectly co-cultured U251 cells using distinctly labeled anti-GFAP and anti-Tuj 1 antibodies, showing significant GFAP protein expression in the co-cultured U251 cells with neural morphology whereas U251 cells (spindle morphology) do not express GFAP.
- Results of proliferation assay of U251 cells, U251-piPSCs and indirectly co-cultured U251 cells by Ki-67 immunostaining show significantly reduced proliferation of U251-piPSCs and the co-cultured U251 cells, Figure 5C .
- Results of migration assays, Figure 5D , and invasion assays, Figure 5E of U251 cells, U251-piPSCs, directly co-cultured U251 cells at 1:1 and 8:1 ratios (U251:U251-piPSCs), show significantly reduced migration and invasion of the U251 cells after co-cultures with U251-piPSCs (p ⁇ 0.005).
- Co-culture of patient-derived primary brain tumor cells, GBM (12-14), with U251-piPSCs also causes a mesenchymal-to-epithelial transition and reduced tumorigenicity of the co-cultured patient-derived primary brain tumor cells - a bystander effect of U251-piPSCs.
- Tumor volume (mm 3 ) of intracranial-implanted rats with either 9L cells or 9L-piPSCs, n 10 was measured at day 14, see Figure 6A .
- Tumor weight in grams of subcutaneously-implanted rats with 9L cells and 9L-piPSCs was measured at day 25 after 4T1-cell implantation, n 6, see Figure 6B .
- Results showed a significantly reduced volume of the intracranial 9L-piPSC tumors and a significantly reduced weight of the subcutaneous 9L-piPSC tumors as compared with those of 9L-tumors, indicating a significantly reduced tumorigenicity of 9L-cells after cell reprogramming into 9L-piPSCs.
- 4T1 and 4T1-piPSC tumor growth were measured by tumor volume, Figure 6C , and tumor weight, Figure 6D , at day 25 after 4T1- and 4T1-piPSC implantation, indicating a significant tumor stasis of 4T1 cells after the cells were reprogrammed into 4T1-piPSCs.
- a Kaplan-Meier survival curve of the mice implanted with 4T1 cells and 4T1-piPSCs in the #4 fat pads, Figure 6F demonstrates a significantly prolonged survival of the 4T1-piPSC bearing mice during this 250-day survival experiment.
- Tumor cell derived piPSCs differentiate into different normal tissues in vivo depending on different differentiating tissue environments.
- H&E stains of the brain tissue sections of 9L-intracranial implanted rats showed major glioma angiogenesis into normal brain tissues and severe bleeding inside brain tumors, whereas much less angiogenesis and bleeding were observed in the 9L-piPSC-intracranial implanted rats.
- 9L-piPSC-intracranial implanted rats also showed newly differentiated neural rosettes near the tumors in the brain.
- H&E stain of the tumor tissue slides of subcutaneouslyimplanted rats with 9L-piPSCs showed immature sweat glands with cuboidal and low columnar epithelial cells and melanocytes with brown color of melanin within the tumors.
- H&E stains of tumor tissue slides of rats subcutaneously implanted with 9L-piPSCs also showed skin epithelium with two layers of epidermis and early simple columnar epithelial cells with longer shape and nuclei in the base of the cells.
- H&E staining of the tumor masses of the 4T1-piPSC-bearing mice showed in vivo differentiation of the implanted 4T1-piPSCs into normal breast tissues including adipocytes including both brown and white adipocytes and mature and immature mammary ducts.
- tumor cell derived-piPSCs differentiate into different normal tissue cells in vivo depending on different differentiating tissue environments.
- Lineage tracing shows tumor cell derived piPSCs differentiate into normal tissues.
- GFP-expressing 9L- and 4T1-cells were prepared.
- GFP-9L-piPSCs and GFP-4T1-piPSCs were prepared.
- adiponectin an adipocyte marker
- cytokeratin 8, 14, 18 CK8, 14, 18
- cytokeratin 5,8 CK5,8
- H&E stain of both the center and edges of tumor mass of the 4T1-piPSC-bearing mice showed appearance of potential adipocytes and immature mammary ducts in the tumor mass.
- Immunostains of the tumor tissue sections of the 4T1-piPSC-bearing mice with anti-CK8,18,14 and anti-CK5,8 antibodies showed CK8,18,14- and anti-CK5,8-positive immunostaining that overlapped with green fluorescence from the GFP-expressing cells. Only overlapping CK8,18,14- or anti-CK5,8-positive and GFP fluorescence were observed in the tissue sections in cells with morphology of mammary ducts, indicating presence of immature mammary ducts that originated from differentiation of the implanted GFP-4T1-piPSCs, since these mammary ducts expressed GFP.
- Tumor growth was measured by volume, see Figure 7A and tumor weight in grams, see Figure 7B .
- the rats were sacrificed at day 23 and tumors were weighed. This data indicates that QQ-SON treatment induced in situ cell reprogramming that results in tumor stasis.
- 4T1 cells (2 x 10 4 cells/50 ⁇ l) were implanted into the #4 fat pads of 2-3 month old female BALB/c mice (20 grams). 4T1 breast tumors were observed at day 5-7 after cell implantation. The tumor volume and body weight of the mice were monitored every day. At day 25, the mice were sacrificed and the tumors were weighed. For the survival experiment, animals were sacrificed once they reached endpoints including tumor burden ( ⁇ 2 gram), metastasis causing labored breath, uncontrollable pain, etc.
- tumor burden ⁇ 2 gram
- metastasis causing labored breath
- uncontrollable pain etc.
- QQ-SON proteins Various dosages of QQ-SON proteins were administered, 0.5 ⁇ g QQ-modified SON proteins/mouse, 1.25 ⁇ g QQ-modified SON proteins/mouse, or 2.5 ⁇ g QQ-modified SON proteins/mouse, and compared with QQ-PBS control. Efficacy was determined by measurement of tumor volume over a 25-day time course, Figure 7D , and measurement of tumor weight in grams, Figure 7E , at day 25.
- QQ-SON protein treatment caused major tumor stasis without primary tumor removal.
- mice were analyzed to determine number and percentage of metastases in the lung, Figures 7I and 7M , lymph nodes, Figures 7J and 7N , liver, Figures 7K and 7O , and spleen, Figures 7L and 7P , of the QQ-SON and QQ-PBS treated 4T1-bearing mice without primary tumor removal as observed by MRI at indicated days.
- QQ-SON treated mice displayed metastasis at much later dates after 4T1-cell implantation and much less metastatic lesions in the lung, lymph nodes and no metastasis lesion was observed in the liver and spleen. This data indicates a major metastasis inhibition in the 4T1-bearing mice caused by QQ-SON protein treatment without primary tumor removal.
- H&E stains of a 9L-tumor tissue slides of a rat treated with QQ-reagents in PBS buffer for 18 daily treatments showing uniform tumor cells with extensive angiogenesis. Immunostains of a nearby tissue slide with anti-VE-cadherin antibody confirmed angiogenesis. This rat was sacrificed at day 26 after subcutaneous 9L cell implantation with a tumor of 13.5 cm 3 (around 15.5 g). In contrast, H&E stains of a tumor tissue slide of a rat treated with QQ-SON protein for 18 daily treatments showed different cell zones including tumor cell zone, connective tissue zone and fibroblast zone. This rat was sacrificed at day 49 after subcutaneous 9L cell implantation and its tumor was significantly reduced in size to 0.2 cm 3 (around 0.6 g).
- Immunostain of the fibroblast zone of a nearby tumor tissue slide of the same rat using an anti-a-procollagen, a fibroblast marker, antibody confirmed the fibroblast zone (positively stained) and tumor cell zone (negatively stained).
- Immunostains of the tumor tissue slides of the same rat treated with QQ-SON proteins for 18 daily treatments using anti-GFAP and anti-Tuj 1 antibodies showed positive stains of both markers with neuronal cell morphology and neural rosette formation. This data indicates that the injected QQ-SON proteins induced in situ generation of transient 9L-piPSCs that differentiate into non-cancerous cells including neuronal lineage cells.
- H&E stains of 4T1-tumor tissue slides of the mice treated with QQ-SON protein also showed adipocytes and mammary duct, which were immunostained positive with adiponectin and cytokaratin 5/8/14, indicating that the injected QQ-SON protein also induced in situ 4T1-tumor cell reprogramming inside the primary tumor into 4T1-piPSCs that differentiate into breast tissue.
- QQ-SON treatment significantly enhances the genome stability of the treated 9L-cells in vivo.
- SKY genome analysis of explanted cells of two subcutaneous 9L-tumor-bearing rats, both treated with QQ-SON protein for 18-days was performed.
- One rat (#12) displayed major response to the QQ-SON treatment and tumor started to shrink. Before the tumor disappeared, this rat was sacrificed and the tumor collected for both explants and tumor tissue slides.
- Another rat (#15) displayed no response to the QQ-SON protein treatment and tumor continued to grow to reach the ending point (> 12 cm 3 ). This rat was also sacrificed and explants and tumor tissue slides were prepared.
- the cells from the explant of #15 rat grew rapidly and reached confluency in 3-days. The cells displayed typical 9L-cell spindle morphology. However, the cells from the explant of #12 rat grew very slowly and only two-weeks later some cells with neural morphology with some colonies were observed. Immunostains of the tumor tissue slides with GFAP and Tuj I showed positive stains for both markers for those cells that displayed neural morphology in #12 rat, but negative stains for these two markers for #15 rat. Additional immunostains with ⁇ -catenin, CK5/6, E-cadherin, Lefty, Nodal and Cripto-1 showed opposite results for #12 and #15 rats.
- tumor tissue slides of #12 rat showed positive stains of CK5/6, E-cadherin, Lefty and ⁇ -catenin, a negative stain was observed in the tumor tissue slides of #15 rat.
- Lefty and E-cadherin co-stained in the same areas of the tumor tissue sections as well as CK5/6 and E-cadherin.
- the tumor tissue slides of #15 rat showed positive stains for Nodal and Cripto-1, but those tissue sections of #12 showed negative stains for these two markers.
- NCCAs non-clonal chromosomal aberrations
- CCAs clonal chromosomal aberrations
- NCCAs represent the level of genome instability while CCAs represent relative stability
- these data suggest that the tumor that did not respond to QQ-SON protein treatment (rat #15) displayed higher levels of genome heterogeneity than those of the tumor (rat #12) that showed a good response to the QQ-SON treatment.
- This result indicates that the protein-induced in situ cell reprogramming significantly enhances genome stability of the treated cancer cells, indicating cell conversion of malignant cancer cells into non-cancerous cells.
- Table 4 tumors that respond to the QQ-SON protein treatment (#12) display higher genome stability than a tumor that did not respond (#15); NCCA: non-clonal chromosomal aberrations; CCA: clonal chromosomal aberrations Rat #mitotic images # chromosomes # NCCAs % NCCAs # CCAs % CCAs #12 20 64 7 35 4 20 #15 20 60 14 70 3 15
- QQ-SON induced cell-converting cancer therapy mediated by protein-induced in situ cell reprogramming caused cancer cure of subcutaneous 9L-tumor bearing rats and late stage 4T1-bearing mice after surgical removal of primary tumors.
- Subcutaneous implantation of 9L-cells into Fisher rats was performed to generate tumor-bearing rats.
- Five days after tumor cell implantation daily intratumor injections of QQ-modified SON (QQ-SON) proteins were performed.
- QQ-PBS QQ-modified SON
- QQ-PBS QQ-modified SON
- QQ-PBS PBS
- QQ-PBS PBS
- a 90-day survival experiment was performed following a 18 daily intratumoral treatment regimen using QQ-SON proteins at 10 ⁇ g/mouse/day. During treatments, significantly reduced tumor growth in all treated rats was observed. After 18 daily treatments, 50% of the treated rats displayed diminished tumor volume over time, and no palpable tumor was present in these animals. The remaining treated rats displayed significantly slower tumor growth.
- Tumor recurrence was observed in three treated rats at day 32, 43 and 62, with a median recurrence of 45 ⁇ 13 days.
- the recurrent tumors grew very aggressively and reached a volume of > 12 cm 3 in 5-7 days (Table 5, Treatment 1).
- the fourth glioma-cured rat remained tumor-free for more than 30 months without evidence of teratoma formation.
- the tumor-cured rats from both treatments 2 and 3 survived for more than 15-months so far without tumor recurrence and without teratoma formation.
- mice Group Tumor size at surgery (mm 3 ) Primary Tumor Recurrence Day detecting lung lesion Day of lung lesions disappeared or cause of death Survival Day Alive 10-23-2014) Red 1 Control 114 No 16 Metastasis 46 Red 2 Control 125 No 16 Metastasis 46 Red 3 Control 60.5 No 16 Metastasis 44 Red 4 Control 25.5 No 16 Metastasis 44 Blue 1 Treatment 6.5 No 16 Inflammation 47 Blue 2 Treatment 20.5 No 16 Stasis 110 Blue 3 Treatment 3.5 No 16 74 267 Blue 4 Treatment 60.5 No 16 Metastasis 49 Blue 5 Treatment 33.5 No 16 59 267 Green 1 Treatment 20 No 16 60 267 Green 2 Treatment 18.5 No 16 Inflammation 75 Green 3 Treatment 15.5 No 16 60 267 Green 4 Treatment 54 No 16 Metastasis position 45 Green 5 Treatment 53 No 16 Inflammation 54
- Figure 8 is a Kaplan-Meier survival curve (250-day survival) of 4T1-breast cancer bearing mice after surgical removal of the primary 4T1-breast cancer at day 18.
- These 4T1 breast cancer bearing mice were treated with QQ-PBS (Control) and QQ-SON proteins (Treatment) at day 6 after 4T1-cell implantation into the #4 fat pad of female BALB/c mice.
- the primary tumors were palpable around day 5 and surgically removed at day 18.
- the QQ-PBS/QQ-SON treatment was performed daily by both intra-tumoral (5 ⁇ g/mouse/day) and intraperitoneal injections (25 ⁇ g/mouse/day).
- Day 0 in the Kaplan-Meier survival curve of Figure 8 is the day when the surgery was performed at day 18.
- a small population of mice displayed tumor recurrence due to incomplete tumor removal. These mice were treated with QQ-SON protein or QQ-PBS via intra-tumoral injections and their survival were also compared (dotted survival curves). For those mice without tumor recurrence, their survival curves are shown in solid lines. Mice that survived for this entire 250-day survival experiment without tumor recurrence are considered tumor-cured mice. Tumorcure has been achieved in 61% of population of treated mice.
- QQ-SON-induced in situ cell reprogramming of the cancer cells inside the tumor to generate transient piPSCs that differentiate into different non-cancerous cells within that tissue is demonstrated.
- the types of the differentiated non-cancerous cells depend on specific tissue environment.
- This inter-play between QQ-SON-induced in situ cell reprogramming and tissue environment induced differentiation precisely regulates generation of transient piPSCs inside tumor and induced differentiation, preventing tumor and teratoma formation.
- This safe protein-induced in situ cell reprogramming technology in situ generates stem cells and which then differentiate into normal cells induced by tissue environment to replace diseased cells for treatment of many diseases and injuries.
- SRY sex determining region Y-box 2 (SOX2) (NM_003106) SEQ ID NO:1 (protein) and SEQ ID NO:65 (DNA)
- POU5F1 Homo sapiens POU class 5 homeobox 1 (POU5F1) also known as Oct4 (NM_002701) SEQ ID NO:2 (protein) and SEQ ID NO:66 (DNA)
- Nanog homeobox (NM_024865) SEQ ID NO:3 (protein) and SEQ ID NO:67 (DNA)
- Homo sapiens lin-28 homolog A (C. elegans) (LIN28A) (NM_024674) SEQ ID NO:4 (protein) and SEQ ID NO:68 (DNA)
- Krueppel-like factor 4 (Klf4) (NP_004226) SEQ ID NO:5 (protein) and SEQ ID NO:69 (DNA)
- NP_002458 Homo sapiens c-MYC (NP_002458) SEQ ID NO:6 (protein) and SEQ ID NO:70 (DNA)
- GATA4 GATA binding protein 4 (NM_002052)
- SEQ ID NO:7 protein
- SEQ ID NO:71 DNA
- HAND2 Homo sapiens heart and neural crest derivatives expressed 2 (HAND2) (NM_021973) SEQ ID NO:8 (protein) and SEQ ID NO:72 (DNA)
- MEF2C myocyte enhancer factor 2C
- SEQ ID NO:9 protein
- SEQ ID NO:73 DNA
- Human transcription factor TBX5 (U80987) SEQ ID NO:10 (protein) and SEQ ID NO:74 (DNA)
- NEUROG3 Homo sapiens neurogenin 3 (NEUROG3) (NM_020999.3) SEQ ID NO:11 (protein) and SEQ ID NO:75 (DNA)
- PAX4 Homo sapiens paired box 4 (PAX4) (NM 006193.2) SEQ ID NO:12 (protein) and SEQ ID NO:76 (DNA)
- PDX1 pancreatic and duodenal homeobox 1 (PDX1) (NM_000209.3) SEQ ID NO:13 (protein) and SEQ ID NO:77 (DNA)
- SLUG Homo sapiens zinc finger protein SLUG (SLUG) gene (AF084243.1) SEQ ID NO:15 (protein) and SEQ ID NO:79 (DNA)
- v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog A (NM_201589.3) SEQ ID NO:16 (protein) and SEQ ID NO:80 (DNA)
- NEUROD1 Neuronal differentiation 1
- SEQ ID NO:17 protein
- SEQ ID NO:81 DNA
- MYF5 Homo sapiens myogenic factor 5 (MYF5) (NM_005593.2) SEQ ID NO:18 (protein) and SEQ ID NO:82 (DNA)
- PRDM16 Homo sapiens PR-domain-containing protein 16 (PRDM16)(AF294278.1) SEQ ID NO:19 (protein) and SEQ ID NO:83 (DNA)
- PAX6 Homo sapiens paired box 6 (PAX6) (NM_001604.5) SEQ ID NO:20 (protein) and SEQ ID NO:84 (DNA)
- SEQ ID NO:21 Homo sapiens HNF1 homeobox A (HNF1A) (NM_000545.5) SEQ ID NO:21 (protein) and SEQ ID NO:85 (DNA)
- SEQ ID NO:25 Homo sapiens CCAAT/enhancer binding protein (C/EBP), alpha (CEBPA) (NM_001287435.1) SEQ ID NO:25 (protein) and SEQ ID NO:89 (DNA)
- Spi-1 proto-oncogene (PU.1) (NM_001080547.1) SEQ ID NO:26 (protein) and SEQ ID NO:90 (DNA)
- POU3F2 Homo sapiens POU class 3 homeobox 2 (POU3F2) (Brn2) (NM _005604.3) SEQ ID NO:27 (protein) and SEQ ID NO:91 (DNA)
- Homo sapiens forkhead box G1 (FOXG1) (NM_005249.4) SEQ ID NO:28 (protein) and SEQ ID NO:92 (DNA)
- SLC7A10 gene Homo sapiens mRNA for ASC1 protein (SLC7A10 gene) (AJ277731.1) SEQ ID NO:29 (protein) and SEQ ID NO:93 (DNA)
- ASCL1 Homo sapiens achaete-scute family bHLH transcription factor 1 (ASCL1) (NM_004316.3) SEQ ID NO:30 (protein) and SEQ ID NO:94 (DNA)
- SEQ ID NO:32 Homo sapiens neurogenin 2 (NEUROG2) (NM _024019) SEQ ID NO:32 (protein) and SEQ ID NO:96 (DNA)
- LIM homeobox transcription factor 1, alpha (LMX1A) (NM_177398) SEQ ID NO:33 (protein) and SEQ ID NO:97 (DNA)
- Homo sapiens HB9 homeobox gene (U07663) SEQ ID NO:34 (protein) and SEQ ID NO:98 (DNA)
- LHX3 Homo sapiens LIM homeobox 3 (LHX3) (NM_178138) SEQ ID NO:35 (protein) and SEQ ID NO:99 (DNA)
- DLX2 distal-less homeobox 2
- SEQ ID NO:36 protein
- SEQ ID NO:100 DNA
- RUNX2 Homo sapiens runt-related transcription factor 2 (RUNX2)(NM_001024630) SEQ ID NO:37 (protein) and SEQ ID NO:101 (DNA)
- GATA6 Homo sapiens GATA binding protein 6 (GATA6) (NM_005257) SEQ ID NO:40 (protein) and SEQ ID NO:104 (DNA)
- GATA1 Homo sapiens GATA binding protein 1(GATA1) (NM_002049) SEQ ID NO:41 (protein) and SEQ ID NO:105 (DNA)
- Fli-1 proto-oncogene NM_002017
- SEQ ID NO:42 protein
- SEQ ID NO:106 DNA
- NGFI-A binding protein 2 EGR1 binding protein 2)(NAB2) (NM_005967) SEQ ID NO:45 (protein) and SEQ ID NO:109 (DNA)
- EGR1 Homo sapiens early growth response 1 (EGR1) (NM_001964) SEQ ID NO:46 (protein) and SEQ ID NO:110 (DNA)
- GFI1 growth factor independent 1 transcription repressor
- PAX5 Homo sapiens paired box 5 (PAX5) (NM_016734) SEQ ID NO:48 (protein) and SEQ ID NO: 112(DNA)
- T-cell-specific T-box transcription factor T-bet mRNA AF241243
- SEQ ID N0:49 protein
- SEQ ID NO: 113 DNA
- GATA3 Homo sapiens GATA binding protein 3 (GATA3) (NM_001002295) SEQ ID NO:50 (protein) and SEQ ID NO:114 (DNA)
- HNF4A hepatocyte nuclear factor 4, alpha
- NM_178849 SEQ ID NO:53 (protein) and SEQ ID NO:117 (DNA)
- EGF1 Homo sapiens squalene epoxidase (ERG1) mRNA, (AF098865) SEQ ID NO:55 (protein) and SEQ ID NO:119 (DNA)
- Homo sapiens ets variant 2 (ETV2/ER71), (NM_014209) SEQ ID NO:56 (protein) and SEQ ID NO:120 (DNA)
- GATA2 Homo sapiens GATA binding protein 2 (GATA2) (NM_001145661) SEQ ID NO:57 (protein) and SEQ ID NO:121 (DNA)
- HEY1 Homo sapiens hes-related family bHLH transcription factor with YRPW motif 1 (HEY1) (NM_012258) SEQ ID NO:58 (protein) and SEQ ID NO:122 (DNA)
- Homo sapiens forkhead box C1 (FOXC1) (NM_001453) SEQ ID NO:60 (protein) and SEQ ID NO:124 (DNA)
- Homo sapiens forkhead box C2 (MFH-1, mesenchyme forkhead 1)(FOXC2) (NM_005251) SEQ ID NO:61 (protein) and SEQ ID NO:125 (DNA)
- SEQ ID NO:62 Homo sapiens SRY (sex determining region Y)-box 7 (SOX7) NM_031439 SEQ ID NO:62 (protein) and SEQ ID NO:126 (DNA)
- compositions and methods described herein are presently representative of preferred embodiments, and are exemplary.
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PL14855040T PL3060237T3 (pl) | 2013-10-25 | 2014-10-27 | Zmodyfikowane białko przeprogramowujące do stosowania w leczeniu raka |
EP21187708.9A EP3954381A1 (en) | 2013-10-25 | 2014-10-27 | Methods, systems and compositions relating to cell conversion via protein induced in-vivo cell reprogramming |
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